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1.  CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait 
PLoS Genetics  2009;5(5):e1000487.
We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.
Author Summary
We identified a homozygous missense mutation (S100P) in the gene encoding carbonic anhydrase VIII in a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. The affected persons walk on their hands and feet with their legs held straight with a “bear-like” gait. Our results show that the mutation S100P induces proteasome-mediated degradation with a severe reduction of the level of CA8 protein. The waddles (wdl) mouse, a spontaneous animal model with ataxia, was previously shown to harbor a 19-bp deletion in Ca8 that leads to an almost complete lack of detectable Ca8 protein, resulting in abnormalities in cerebellar synaptic transmission. Therefore, we speculate that the reduction in CA8 protein concentration associated with the S100P mutation could result in similar pathophysiological effects. With the current report, alterations at three gene loci (CA8, VLDLR, and a yet-to-be discovered gene on chromosome 17p) have been reported to be associated with quadrupedal gait. It is unknown whether quadrupedal gait is related to specific molecular abnormalities or is an adaptive response to ataxia in some circumstances. However, we note that ataxia associated with mutations at all three loci is congenital and also associated with mental retardation, which is not generally a feature of other hereditary ataxias.
doi:10.1371/journal.pgen.1000487
PMCID: PMC2677160  PMID: 19461874
2.  Mutations in VLDLR as a Cause for Autosomal Recessive Cerebellar Ataxia with Mental Retardation (Dysequilibrium Syndrome) 
Journal of child neurology  2009;24(10):1310-1315.
Dysequilibrium syndrome (DES) is a genetically heterogeneous condition that combines autosomal recessive, non-progressive cerebellar ataxia with mental retardation. Here we report the first patient heterozygous for two novel mutations in VLDLR. An 18-month old girl presented with significant hypotonia, global developmental delay, and truncal and peripheral ataxia. MR imaging of the brain demonstrated hypoplasia of the inferior cerebellar vermis and hemispheres, small pons, and a simplified cortical sulcation pattern. Sequence analysis of the VLDLR gene identified a nonsense and missense mutation. Six mutations in VLDLR have now been identified in five families with a phenotype characterized by moderate-to-profound mental retardation, delayed ambulation, truncal and peripheral ataxia and occasional seizures. Neuroanatomically, the loss-of-function effect of the different mutations is indistinguishable. VLDLR-associated cerebellar hypoplasia is emerging as a panethnic, clinically and molecularly well-defined genetic syndrome.
doi:10.1177/0883073809332696
PMCID: PMC2849979  PMID: 19332571
VLDLR; Cerebellar hypoplasia; Dysequilibrium syndrome
3.  Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion 
Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans.
doi:10.1038/ejhg.2012.170
PMCID: PMC3573203  PMID: 22892528
ATP8A2; cerebellar hypoplasia; targeted next-generation sequencing; quadrupedal locomotion; CAMRQ
4.  Challenges of diagnostic exome sequencing in an inbred founder population 
Exome sequencing was used as a diagnostic tool in a Roma/Gypsy family with three subjects (one deceased) affected by lissencephaly with cerebellar hypoplasia (LCH), a clinically and genetically heterogeneous diagnostic category. Data analysis identified high levels of unreported inbreeding, with multiple rare/novel “deleterious” variants occurring in the homozygous state in the affected individuals. Step-wise filtering was facilitated by the inclusion of parental samples in the analysis and the availability of ethnically matched control exome data. We identified a novel mutation, p.Asp487Tyr, in the VLDLR gene involved in the Reelin developmental pathway and associated with a rare form of LCH, the Dysequilibrium Syndrome. p.Asp487Tyr is the third reported missense mutation in this gene and the first example of a change affecting directly the functionally crucial β-propeller domain. An unexpected additional finding was a second unique mutation (p.Asn494His) with high scores of predicted pathogenicity in KCNV2, a gene implicated in a rare eye disorder, retinal cone dystrophy type 3B. This result raised diagnostic and counseling challenges that could be resolved through mutation screening of a large panel of healthy population controls. The strategy and findings of this study may inform the search for new disease mutations in the largest European genetic isolate.
doi:10.1002/mgg3.7
PMCID: PMC3865571  PMID: 24498604
Diagnostic exome sequencing; dysequilibrium syndrome; founder mutations; Roma/Gypsies; VLDLR
5.  The Role of Vldlr in Intraretinal Angiogenesis in Mice 
The study further demonstrates the essential role of Vldlr in the regulation of intraretinal angiogenesis in mice and suggests that it probably mediates an antiangiogenic signal to prevent the migration of vascular endothelial cells into the photoreceptor cell layer.
Purpose.
To identify and characterize the r26 mouse line, which displays depigmented patches in the retina, and to determine the causative gene mutation and study the underlying mechanism.
Methods.
Fundus examination, fluorescein angiography, histology, and immunostaining were used to determine the retinal phenotypes. Genome-wide linkage analysis, DNA sequencing, and an allelic test were used to identify the causative gene mutation. Wild-type and mutant gene products were examined by Western blot and transient transfection.
Results.
Homozygous r26/r26 mice displayed depigmented patches in the fundus that overlapped the hyperfluorescent spots in the angiogram. Histology showed overgrown retinal vessels in the subretinal space. Immunostaining verified the presence of endothelial cells in the photoreceptor layer. Chromosome mapping and DNA sequencing revealed a point mutation, c.2239C>T, in the very-low-density lipoprotein receptor (Vldlr) gene. An allelic test in Vldlr knockout (−/−) mice confirmed that r26/− mice display a phenotype similar to that of r26/r26 mice. The Vldlr protein was predominantly localized at the plasma membrane of transfected cells, whereas the truncated Vldlr was diffusely expressed in the cell cytosol. The r26 truncated Vldlr was undetectable in mutant retinas by Western blot.
Conclusions.
The r26 is a recessive mutant caused by a missense mutation in the Vldlr gene. This results in a truncated Vldlr protein that lacks the C-terminal 127 amino acid residues including the single transmembrane domain and fails to localize at the plasma membrane. Thus, the r26 is a loss-of-function Vldlr mutation. Vldlr on the cell surface probably mediates an antiangiogenic signal to prevent retinal endothelial cells from migrating into the photoreceptor cell layer.
doi:10.1167/iovs.10-7082
PMCID: PMC3176028  PMID: 21757581
6.  CAMOS, a nonprogressive, autosomal recessive, congenital cerebellar ataxia, is caused by a mutant zinc-finger protein, ZNF592 
European Journal of Human Genetics  2010;18(10):1107-1113.
CAMOS (Cerebellar Ataxia with Mental retardation, Optic atrophy and Skin abnormalities) is a rare autosomal recessive syndrome characterized by a nonprogressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities. Using homozygosity mapping in a large inbred Lebanese Druze family, we previously reported the mapping of the disease gene at chromosome 15q24–q26 to a 3.6-cM interval between markers D15S206 and D15S199. Screening of candidate genes lying in this region led to the identification of a homozygous p.Gly1046Arg missense mutation in ZNF592, in all five affected individuals of the family. ZNF592 encodes a 1267-amino-acid zinc-finger (ZnF) protein, and the mutation, located within the eleventh ZnF, is predicted to affect the DNA-binding properties of ZNF592. Although the precise role of ZNF592 remains to be determined, our results suggest that ZNF592 is implicated in a complex developmental pathway, and that the mutation is likely to disturb the highly orchestrated regulation of genes during cerebellar development, by either disrupting interactions with target DNA or with a partner protein.
doi:10.1038/ejhg.2010.82
PMCID: PMC2987462  PMID: 20531441
CAMOS; missense mutation; ZNF592; C2H2 zinc-finger domain; cerebellar ataxia; nonprogressive
7.  AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome 
Journal of Medical Genetics  2005;43(4):334-339.
Background
Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1).
Methods
We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis.
Results
We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions.
Conclusions
Overall, 11% of subjects had AHI1 mutations, while ∼2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype‐phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.
doi:10.1136/jmg.2005.036608
PMCID: PMC2563230  PMID: 16155189
AHI1 ; cerebellar vermis hypoplasia; Joubert syndrome; nephronophthisis;  NPHP1
8.  Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases 
PLoS Genetics  2011;7(10):e1002325.
We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other “mitochondrial” features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.
Author Summary
Mitochondria are cellular organelles important for converting sugar or fats into energy that cells can use for their functions and survival. Many neurological diseases are the result of mitochondrial dysfunction as affected cells are unable to cope with lowered energy supplies and increased oxidative stress. These deficiencies cause accumulation of cellular damage and eventually cell death. Spastic ataxias are neurological disorders involving cells with large energy requirements, the cerebellar Purkinje cells and the cerebral upper motor neurons. When these cells function improperly or die, individuals develop symptoms of incoordination (ataxia) and abnormal muscle tone in their legs (spastic paraplegia). Using emerging techniques of whole-exome sequencing we discovered that homozygous mutations in the AFG3L2 gene caused spastic ataxia in two brothers of a consanguineous family. AFG3L2 encodes a subunit of mitochondrial matrix proteases (m-AAA proteases) that regulate the functional integrity of mitochondria. Heterozygous mutations in AFG3L2 were previously found to cause a disorder involving the Purkinje cells of the cerebellum resulting in ataxia. Interestingly, another isoform of m-AAA proteases consists of AFG3L2 complexing with paraplegin, a similar protein associated with a hereditary spastic paraplegia. Our analysis provides insight into why different mutations in m-AAA protease subunits cause different neurological disorders.
doi:10.1371/journal.pgen.1002325
PMCID: PMC3192828  PMID: 22022284
9.  Two families with quadrupedalism, mental retardation, no speech, and infantile hypotonia (Uner Tan Syndrome Type-II); a novel theory for the evolutionary emergence of human bipedalism 
Two consanguineous families with Uner Tan Syndrome (UTS) were analyzed in relation to self-organizing processes in complex systems, and the evolutionary emergence of human bipedalism. The cases had the key symptoms of previously reported cases of UTS, such as quadrupedalism, mental retardation, and dysarthric or no speech, but the new cases also exhibited infantile hypotonia and are designated UTS Type-II. There were 10 siblings in Branch I and 12 siblings in Branch II. Of these, there were seven cases exhibiting habitual quadrupedal locomotion (QL): four deceased and three living. The infantile hypotonia in the surviving cases gradually disappeared over a period of years, so that they could sit by about 10 years, crawl on hands and knees by about 12 years. They began walking on all fours around 14 years, habitually using QL. Neurological examinations showed normal tonus in their arms and legs, no Babinski sign, brisk tendon reflexes especially in the legs, and mild tremor. The patients could not walk in a straight line, but (except in one case) could stand up and maintain upright posture with truncal ataxia. Cerebello-vermial hypoplasia and mild gyral simplification were noted in their MRIs. The results of the genetic analysis were inconclusive: no genetic code could be identified as the triggering factor for the syndrome in these families. Instead, the extremely low socio-economic status of the patients was thought to play a role in the emergence of UTS, possibly by epigenetically changing the brain structure and function, with a consequent selection of ancestral neural networks for QL during locomotor development. It was suggested that UTS may be regarded as one of the unpredictable outcomes of self-organization within a complex system. It was also noted that the prominent feature of this syndrome, the diagonal-sequence habitual QL, generated an interference between ipsilateral hands and feet, as in non-human primates. It was suggested that this may have been the triggering factor for the attractor state “bipedal locomotion” (BL), which had visual and manual benefits for our ape-like ancestors, and therefore enhancing their chances for survival, with consequent developments in the psychomotor domain of humans. This was put forward as a novel theory of the evolution of BL in human beings.
doi:10.3389/fnins.2014.00084
PMCID: PMC4001073  PMID: 24795558
Uner Tan syndrome; ataxia; quadrupedalism; evolution; complex systems; self-organization
10.  Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development 
PLoS Genetics  2012;8(12):e1003074.
β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.
Author Summary
β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Mutations in β-III spectrin cause spinocerebellar ataxia type 5 (SCA5), sometimes called Lincoln ataxia because it was first described in the relatives of United States President Abraham Lincoln. This is generally an adult-onset progressive cerebellar disorder. Recessive mutations have not previously been described in any of the brain spectrins. We identified a homozygous mutation in SPTBN2, which causes a more severe disorder than SCA5, with a developmental cerebellar ataxia, which is present from childhood; in addition there is marked cognitive impairment. We call this novel condition SPARCA1 (Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1). This condition could be caused by two separate gene mutations; but we show, using a combination of genome-wide mapping, whole-genome sequencing, and detailed behavioural and neuropathological analysis of a β-III spectrin mouse knockout, that both the ataxia and cognitive impairment are caused by the recessive mutations in β-III spectrin. SPARCA1 is one of a family of neuronal spectrinopathies and illustrates the importance of spectrins in brain development and function.
doi:10.1371/journal.pgen.1003074
PMCID: PMC3516553  PMID: 23236289
11.  Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p 
Journal of Medical Genetics  2005;43(5):461-464.
Background
Congenital hereditary non‐progressive hypoplasia of the cerebellum is a rare condition, frequently associated with other neuropathology such as lissencephaly. Clinically, the condition is associated with variable degrees of mental retardation, microcephaly, seizures, and movement disorders due to ataxia. In severe cases, patients are unable to ambulate independently, but nevertheless do use bipedal locomotion.
Methods and Results
Here we present a family with seven affected members, five of whom never learned to walk on two legs but have fully adapted to quadrupedal palmigrade locomotion. These subjects show signs of cerebellar ataxia and are mentally retarded. MRI analysis demonstrated hypoplasia of the cerebellum and the cerebellar vermis as well as a small nucleus dentatus and a thin corpus callosum but no other malformations. We show, by a genome‐wide linkage scan, that quadrupedal locomotion is a recessive trait linked to chromosome 17p.
Conclusions
Our findings have implications for understanding the neural mechanism mediating bipedalism, and, perhaps, the evolution of this unique hominid trait.
doi:10.1136/jmg.2005.040030
PMCID: PMC2564522  PMID: 16371500
bipedality; cerebellar hypoplasia; linkage; quadrupedal locomotion
12.  A SEL1L Mutation Links a Canine Progressive Early-Onset Cerebellar Ataxia to the Endoplasmic Reticulum–Associated Protein Degradation (ERAD) Machinery 
PLoS Genetics  2012;8(6):e1002759.
Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (praw = 1.1×10−7, pgenome = 7.5×10−4). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)–associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD–mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders.
Author Summary
Hereditary ataxias are a heterogeneous group of rare disorders characterized by progressive cerebellar neurodegeneration. Several causative mutations have been identified in various forms of human ataxias. In addition to humans, inherited ataxias have been described in several other species, including the domestic dog. In this study, we have studied the clinical and genetic properties of cerebellar ataxia in the Finnish Hound dog breed. The breed suffers from a progressive ataxia that has an early onset before the age of 3 months. Affected puppies have difficulties in coordinating their movements and balance, and have to be euthanized due to rapidly worsening symptoms. Our pedigree analysis suggested an autosomal recessive mode of inheritance, which was confirmed by identifying a homozygous mutation in the SEL1L gene through genome-wide association and linkage analyses. The SEL1L protein functions in a protein quality control pathway that targets misfolded proteins to degradation in the endoplasmic reticulum. Mutations in the SEL1L gene have not been previously found in ataxias. Our study indicates SEL1L as a novel candidate gene for human childhood ataxias, establishes a large animal model to investigate mechanisms of cerebellar neurodegeneration, and enables carrier screening for breeding purposes.
doi:10.1371/journal.pgen.1002759
PMCID: PMC3375262  PMID: 22719266
13.  Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia 
Background
Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family.
Methods and Results
Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified.
Conclusions
ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.
doi:10.1186/1750-1172-7-67
PMCID: PMC3545966  PMID: 22986007
Congenital nonprogressive spinocerebellar ataxia; Spinocerebellar ataxia type 29; Cerebellar atrophy; ITPR1; Gene identification
14.  Cloning and expression profiling of the VLDLR gene associated with egg performance in duck (Anas platyrhynchos) 
Background
The very low density lipoprotein receptor gene (VLDLR), a member of the low density lipoprotein receptor (LDLR) gene family, plays a crucial role in the synthesis of yolk protein precursors in oviparous species. Differential splicing of this gene has been reported in human, rabbit and rat. In chicken, studies showed that the VLDLR protein on the oocyte surface mediates the uptake of yolk protein precursors into growing oocytes. However, information on the VLDLR gene in duck is still scarce.
Methods
Full-length duck VLDLR cDNA was obtained by comparative cloning and rapid amplification of cDNA ends (RACE). Tissue expression patterns were analysed by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR). Association between the different genotypes and egg performance traits was investigated with the general linear model (GLM) procedure of the SAS® software package.
Results
In duck, two VLDLR transcripts were identified, one transcript (variant-a) containing an O-linked sugar domain and the other (variant-b) not containing this sugar domain. These transcripts share ~70 to 90% identity with their counterparts in other species. A phylogenetic tree based on amino acid sequences showed that duck VLDLR proteins were closely related with those of chicken and zebra finch. The two duck VLDLR transcripts are differentially expressed i.e. VLDLR-a is mainly expressed in muscle tissue and VLDLR-b in reproductive organs. We have localized the duck VLDLR gene on chromosome Z. An association analysis using two completely linked SNP sites (T/C at position 2025 bp of the ORF and G/A in intron 13) and records from two generations demonstrated that the duck VLDLR gene was significantly associated with egg production (P < 0.01), age of first egg (P < 0.01) and body weight of first egg (P < 0.05).
Conclusions
Duck and chicken VLDLR genes probably perform similar function in the development of growing oocytes and deposition of yolk lipoprotein. Therefore, VLDLR could be a candidate gene for duck egg performance and be used as a genetic marker to improve egg performance in ducks.
doi:10.1186/1297-9686-43-29
PMCID: PMC3162882  PMID: 21819592
15.  Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics 
Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.
doi:10.1186/1750-1172-6-33
PMCID: PMC3123548  PMID: 21619691
16.  Triple A (Allgrove) syndrome: an unusual association with syringomyelia 
Triple A (Allgrove) syndrome was first described by Allgrove in 1978 in two pairs of siblings. Since then, about 100 cases have been reported, all of them displaying an autosomal recessive pattern of inheritance. Clinical picture is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure. A progressive neurological syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation is often associated. The triple A syndrome gene, designated AAAS, is localized on chromosome 12q13. It consists of 16 exons, encoding for a 546 aminoacid protein called ALADIN (Alacrimia-Achalasia-aDrenal Insufficiency Neurologic disorder).
We report on a 13 year-old boy presenting with Addison’s disease, dysphagia, muscle weakness, excessive fatigue and recent onset gait ataxia. The analysis of the AAAS gene revealed a homozygous missense mutation in exon 12. It was a T > G transversion at nucleotide position 1224, resulting in a change of leucine at amino acid position 381 into arginine (Leu381Arg or L381R). Brain appearance was found normal at magnetic resonance imaging (MRI) and functional spectroscopy analysis showed normal levels of the main metabolites. Spine MRI showed a cystic cavity within the spinal cord (syringomyelia), localized between the sixth cervical vertebra and the first thoracic vertebra. Cerebellar tonsils descended 7 mm caudal to foramen magnum, consistently with a mild type 1 Chiari malformation. Mild posterior inter-vertebral disk protrusions were evident between T9 and T10 and between L4 and L5.
To our knowledge, this is the first report describing type 1 Chiari malformation and multiple spinal cord abnormalities in a patient with Allgrove syndrome.
doi:10.1186/1824-7288-39-39
PMCID: PMC3704905  PMID: 23800107
Allgrove syndrome; Achalasia; Alacrimia; Adrenal failure; Syringomyelia
17.  Twelve Novel Atm Mutations Identified in Chinese Ataxia Telangiectasia Patients 
Neuromolecular Medicine  2013;15:536-540.
Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized mainly by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. This disease is caused by mutations of the ataxia telangiectasia mutated (Atm) gene. More than 500 Atm mutations that are responsible for A-T have been identified so far. However, there have been very few A-T cases reported in China, and only two Chinese A-T patients have undergone Atm gene analysis. In order to systemically investigate A-T in China and map their Atm mutation spectrum, we recruited eight Chinese A-T patients from six unrelated families nationwide. Using direct sequencing of genomic DNA and the multiplex ligation-dependent probe amplification, we identified twelve pathogenic Atm mutations, including one missense, four nonsense, five frameshift, one splicing, and one large genomic deletion. All the Atm mutations we identified were novel, and no homozygous mutation and founder-effect mutation were found. These results suggest that Atm mutations in Chinese populations are diverse and distinct largely from those in other ethnic areas.
doi:10.1007/s12017-013-8240-3
PMCID: PMC3732755  PMID: 23807571
Ataxia telangiectasia; Mutation analysis; Sequencing; MLPA
18.  CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes 
Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
doi:10.1038/ejhg.2009.220
PMCID: PMC2987321  PMID: 20029458
CASK gene; XLMR; intellectual disability; congenital nystagmus
19.  Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3 
As part of a large-scale, systematic effort to unravel the molecular causes of autosomal recessive mental retardation, we have previously described a novel syndrome consisting of mental retardation, coloboma, cataract and kyphosis (Kahrizi syndrome, OMIM 612713) and mapped the underlying gene to a 10.4-Mb interval near the centromere on chromosome 4. By combining array-based exon enrichment and next generation sequencing, we have now identified a homozygous frameshift mutation (c.203dupC; p.Phe69LeufsX2) in the gene for steroid 5α-reductase type 3 (SRD5A3) as the disease-causing change in this interval. Recent evidence indicates that this enzyme is required for the conversion of polyprenol to dolichol, a step that is essential for N-linked protein glycosylation. Independently, another group has recently observed SRD5A3 mutations in several families with a type 1 congenital disorder of glycosylation (CDG type Ix, OMIM 212067), mental retardation, cerebellar ataxia and eye disorders. Our results show that Kahrizi syndrome and this CDG Ix subtype are allelic disorders, and they illustrate the potential of next-generation sequencing strategies for the elucidation of single gene defects.
doi:10.1038/ejhg.2010.132
PMCID: PMC3039499  PMID: 20700148
SRD5A3; next generation sequencing; congenital disorder of glycosylation; mental retardation; autosomal recessive; consanguinity
20.  A rare thyroid hormone receptor beta (THRβ) gene mutation in a 15-year-old girl with thyroid hormone resistance syndrome: a case report 
Introduction
Resistance to thyroid hormone is a rare syndrome, where although the level of thyroid hormone is elevated, the level of thyroid stimulating hormone is not suppressed. The patient in our case report is, to the best of our knowledge, the first with this syndrome identified in Oman.
Case presentation
In one Omani family, a 15-year-old girl of Arabian origin was pre-diagnosed with resistance to thyroid hormone. Blood sample was collected and deoxyribonucleic acid was isolated for molecular genetic testing. The results revealed a rare mutation A268G in the gene for thyroid hormone receptor beta. We believe that this mutation is the cause of the pathology in our patient.
Conclusion
We report the presence of a rare mutation in the thyroid hormone receptor beta gene for the first time in the Omani population. Due to the rates of consanguinity being high among the Omani population, we are aiming to screen our patient’s family members and provide genetic counseling.
doi:10.1186/1752-1947-8-12
PMCID: PMC3901553  PMID: 24393243
Autosomal dominant; Consanguinity; Oman; THRβ; Thyroid hormone resistance
21.  A Family with Mental Retardation, Epilepsy and Cerebellar Hypoplasia Showing Linkage to Chromosome 20p11.21-q11.23 
Case Reports in Neurology  2014;6(1):18-22.
Background
Cerebellar hypoplasia (CH) is a rare malformation caused by various etiologies, usually manifesting clinically as nonprogressive cerebellar ataxia with or without mental retardation. The molecular pathogenesis of the autosomal recessive cerebellar ataxias has a wide range of mechanisms. Differential diagnosis and categorization of the recessive cerebellar ataxias, however, need more specific, biochemical and genetic investigation.
Methods
This study applied whole-genome linkage analysis to study a family with nonprogressive cerebellar ataxia and additional mental retardation, epilepsy, and facial dysmorphic features. Genotyping and linkage analysis was done using the GeneChip Mapping 250K NspI Array (Affymetrix Inc., Santa Clara, Calif., USA) for genome-wide linkage analysis of the genotyping data from the affected children and their parents.
Results
Allegro software version 1.2 was used for multipoint linkage analysis. We assumed an autosomal recessive inheritance pattern and assigned a penetrance of 0.999. Single-nucleotide polymorphism allele frequencies were estimated from the Affymetrix data of the Caucasian family studied. Using these parameters, a theoretical maximum logarithm of the odds score of 2.69 was identified at chromosome 20p11.21-q11.23.
Conclusions
This chromosomal locus is unprecedented in autosomal recessive and nonprogressive ataxia disorder. Further investigation might reveal a new causative gene generating the CH phenotype.
doi:10.1159/000357172
PMCID: PMC3934806  PMID: 24575028
Parametric linkage analysis; Cerebellar hypoplasia; Mental retardation; Logarithm of the odds score
22.  A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients 
Journal of Medical Genetics  2003;40(1):11-17.
Background: The gene encoding fatty acid CoA ligase 4 (FACL4) is mutated in families with non-specific X linked mental retardation (MRX) and is responsible for cognitive impairment in the contiguous gene syndrome ATS-MR (Alport syndrome and mental retardation), mapped to Xq22.3. This finding makes this gene a good candidate for other mental retardation disorders mapping in this region.
Methods: We have screened the FACL4 gene in eight families, two MRX and six syndromic X linked mental retardation (MRXS), mapping in a large interval encompassing Xq22.3.
Results: We have found a missense mutation in MRX68. The mutation (c.1001C>T in the brain isoform) cosegregates with the disease and changes a highly conserved proline into a leucine (p.P375L) in the first luciferase domain, which markedly reduces the enzymatic activity. Furthermore, all heterozygous females showed completely skewed X inactivation in blood leucocytes, as happens in all reported females with other FACL4 point mutations or deletions.
Conclusions: Since the FACL4 gene is highly expressed in brain, where it encodes a brain specific isoform, and is located in hippocampal and cerebellar neurones, a role for this gene in cognitive processes can be expected. Here we report the third MRX family with a FACL4 mutation and describe the development of a rapid enzymatic assay on peripheral blood that we propose as a sensitive, robust, and efficient diagnostic tool in mentally retarded males.
doi:10.1136/jmg.40.1.11
PMCID: PMC1735250  PMID: 12525535
23.  Molecular analysis of CYP1B1 in Omani patients with primary congenital glaucoma: a pilot study 
Molecular Vision  2009;15:1325-1331.
Purpose
To screen cytochrome P4501B1 (CYP1B1) for causative mutations in Omani patients with a clinical diagnosis of primary congenital glaucoma (PCG)
Methods
Nine PCG families were recruited for the study. All patients underwent detailed clinical examinations to confirm the diagnosis of PCG. The families of index patients were also examined. Genealogical information was obtained by pedigree analysis. The primary candidate gene, CYP1B1, was amplified from genomic DNA, sequenced, and analyzed in patients to identify the disease-causing mutations.
Results
Eight of the nine PCG families were consanguineous (89%). Molecular analysis of CYP1B1 showed three distinct mutations, p.G61E, p.D374N, and p.R368H, in seven of nine unrelated PCG index patients (78%). Six patients had homozygous mutations and one had a compound heterozygous mutation. Causative mutations were not identified in two families. In family 4, the index patient was found to be heterozygous for the p.E229K variant. In family 6, although affected individuals were found to be homozygous in the CYP1B1 region, no mutation could be identified.
Conclusions
This study indicates that CYP1B1 could be the predominant cause of PCG in the Omani population (78%). Omani PCG patients show allelic heterogeneity. Further studies are needed to delineate the spectrum of CYP1B1mutations in Omani PCG families and to identify new or modifier genes contributing to the manifestations of PCG in this region.
PMCID: PMC2709423  PMID: 19597567
24.  WDR19: An ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome 
Clinical genetics  2013;84(2):150-159.
Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ~500 arRP mutations in ~20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed ‘sub-clinical’ renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.
doi:10.1111/cge.12196
PMCID: PMC3904424  PMID: 23683095
childhood blindness; IFT144; IFT-A; nephronophtisis; photoreceptors; retinal degeneration; retinitis pigmentosa; Senior-Løken syndrome; WDR19
25.  Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis) 
Journal of medical genetics  2009;47(1):8-21.
Objective
To identify genetic causes of COACH syndrome
Background
COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD).
Methods
In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced.
Results
19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%).
Conclusions
Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.
doi:10.1136/jmg.2009.067249
PMCID: PMC3501959  PMID: 19574260

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