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1.  Centronuclear Myopathy in Labrador Retrievers: A Recent Founder Mutation in the PTPLA Gene Has Rapidly Disseminated Worldwide 
PLoS ONE  2012;7(10):e46408.
Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ∼70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLAcnm mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLAcnm carriers in 13 countries. Haplotype analysis demonstrated that the PTPLAcnm allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM.
PMCID: PMC3465307  PMID: 23071563
2.  Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy 
Human mutation  2012;33(6):949-959.
Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
PMCID: PMC3374402  PMID: 22396310
centronuclear myopathy; congenital myopathy; Charcot–Marie–Tooth neuropathy; DNM2; ADCNM; CMTD1B; DI-CMTB; CMT2M; hereditary motor and sensory neuropathy type II; HMSNII; MTM1; myotubular myopathy; BIN1; RYR1; endocytosis
3.  Mild Functional Differences of Dynamin 2 Mutations Associated to Centronuclear Myopathy and Charcot-Marie-Tooth Peripheral Neuropathy 
PLoS ONE  2011;6(11):e27498.
The large GTPase dynamin 2 is a key player in membrane and cytoskeletal dynamics mutated in centronuclear myopathy (CNM) and Charcot-Marie Tooth (CMT) neuropathy, two discrete dominant neuromuscular disorders affecting skeletal muscle and peripheral nerves respectively. The molecular basis for the tissue-specific phenotypes observed and the physiopathological mechanisms linked to dynamin 2 mutations are not well established. In this study, we have analyzed the impact of CNM and CMT implicated dynamin 2 mutants using ectopic expression of four CNM and two CMT mutations, and patient fibroblasts harboring two dynamin 2 CNM mutations in established cellular processes of dynamin 2 action. Wild type and CMT mutants were seen in association with microtubules whereas CNM mutants lacked microtubules association and did not disrupt interphase microtubules dynamics. Most dynamin 2 mutants partially decreased clathrin-mediated endocytosis when ectopically expressed in cultured cells; however, experiments in patient fibroblasts suggested that endocytosis is overall not defective. Furthermore, CNM mutants were seen in association with enlarged clathrin stained structures whereas the CMT mutant constructs were associated with clathrin structures that appeared clustered, similar to the structures observed in Dnm1 and Dnm2 double knock-out cells. Other roles of dynamin 2 including its interaction with BIN1 (amphiphysin 2), and its function in Golgi maintenance and centrosome cohesion were not significantly altered. Taken together, these mild functional defects are suggestive of differences between CMT and CNM disease-causing dynamin 2 mutants and suggest that a slight impairment in clathrin-mediated pathways may accumulate over time to foster the respective human diseases.
PMCID: PMC3214065  PMID: 22096584
4.  Case report of intrafamilial variability in autosomal recessive centronuclear myopathy associated to a novel BIN1 stop mutation 
Centronuclear myopathies (CNM) describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM) is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM). Autosomal recessive centronuclear myopathy (ARCNM) is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations.
PMCID: PMC3014877  PMID: 21129173
5.  Reducing dynamin 2 expression rescues X-linked centronuclear myopathy 
The Journal of Clinical Investigation  2014;124(3):1350-1363.
Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1–/y). Generation of Mtm1–/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle–specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.
PMCID: PMC3938268  PMID: 24569376
6.  Severe phenotype of a patient with autosomal recessive centronuclear myopathy due to a BIN1 mutation 
Acta Myologica  2009;28(3):91-93.
Centronuclear myopathy (CNM) is a rare hereditary congenital myopathy characterized by muscular hypotonia and abnormal centralization of nuclei in muscle fibers. The autosomal recessive (AR) form presents from birth to childhood, followed by a mild progression of muscle weakness. Despite recently identified genetic loci in the AR form, genotype-phenotype correlations are poorly established. Our index case is a 17 year old boy with recessive CNM causing loss of ambulation at 13 years of age and requiring ventilatory assistance nightly. Recent genetic testing revealed a c.1723A > T mutation in the BIN1 gene. The phenotype of the index case contrasts to previously published cases, where recessive CNM patients have lost ambulation in their 20s and have not required ventilatory assistance. The disease severity of our index case, carrying a c.1723A > T mutation, widens the phenotypic spectrum of AR CNM to include earlier loss of ambulation and respiratory failure.
PMCID: PMC2858945  PMID: 20476667
Centronuclear myopathy; BIN1; phenotype
7.  Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy 
PLoS Genetics  2013;9(6):e1003430.
Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.
Author Summary
The intracellular organization of muscle fibers relies on a complex membrane system important for muscle structural organization, maintenance, contraction, and resistance to stress. Amphiphysin 2, encoded by BIN1, plays a central role in membrane sensing and remodelling and is involved in intracellular membrane trafficking in different cell types. The ubiquitously expressed BIN1, altered in centronuclear myopathy (CNM) and myotonic dystrophy (DM), possesses a muscle-specific exon coding for a phosphoinositide binding domain. We identified splice mutations affecting the muscle-specific BIN1 isoform in humans and dogs presenting a clinically and histopathologically comparable highly progressive centronuclear myopathy. Our functional and ultrastructural data emphasize the importance of amphiphysin 2 in membrane remodeling and suggest that the defective maintenance of the triad structure is a primary cause for the muscle weakness. The canine Inherited Myopathy of Great Danes is the first faithful mammalian model for investigating other potential pathological mechanisms underlying centronuclear myopathy and for testing therapeutic approaches.
PMCID: PMC3675003  PMID: 23754947
8.  Genetics of congenital nemaline myopathy: a study of 10 families. 
Journal of Medical Genetics  1990;27(8):480-487.
In order to investigate the inheritance in congenital nemaline myopathy (CNM), we studied the family histories and pedigrees of 13 patients with CNM from 10 families, and the 20 patients, by physical examination, single fibre electromyography, ultrasonography of muscles, measurement of serum creatine kinase, muscle biopsy, and electrophoresis of muscle proteins. None of the parents was affected. In three families there were two affected children. Of the parents, 15 showed deficiency of type 2B muscle fibres, and all except one father showed some other minor neuromuscular abnormality. These may represent heterozygous manifestations of recessive gene. Most of the ancestors came from sparsely populated rural communities in the west of Finland. We conclude that in the Finnish CNM patients, the mode of inheritance appears to be recessive. Apart from a few instances of dominant inheritance, most cases published also seem compatible with recessive inheritance.
PMCID: PMC1017195  PMID: 2213842
9.  Sporadic Centronuclear Myopathy with Muscle Pseudohypertrophy, Neutropenia, and Necklace Fibers due to a DNM2 mutation 
Neuromuscular disorders : NMD  2010;20(12):801-804.
Dynamin 2 gene (DNM2) mutations result in an autosomal dominant centronuclear myopathy (CNM) and a Charcot-Marie-Tooth (CMT) neuropathy. DNM2-CMT but not DNM2-CNM patients were noted to have neutropenia. We here report a man with paravertebral muscles hypertrophy and mild neutropenia. His muscle biopsy was typical for CNM with additional “necklace” fibers. Sequencing of DNM2 revealed a known heterozygous c.1269C>T (p.Arg369Trp) mutation. Necklace fibers were considered as a pathological hallmark of late onset X-linked CNM due to mutations in MTM1 but have not been observed in DNM2-CNM. The findings broaden the features of DNM2-myopathy.
PMCID: PMC2991611  PMID: 20817456
Centronuclear myopathy; DNM2; dynamin 2; muscle hypertrophy; muscle pseudohypertrophy, necklace fibers; neutropenia
10.  X linked neonatal centronuclear/myotubular myopathy: evidence for linkage to Xq28 DNA marker loci. 
Journal of Medical Genetics  1990;27(5):284-287.
We have studied the inheritance of several polymorphic Xq27/28 DNA marker loci in two three generation families with the X linked neonatal lethal form of centronuclear/myotubular myopathy (XL MTM). We found complete linkage of XLMTM to all four informative Xq28 markers analysed, with GCP/RCP (Z = 3.876, theta = 0.00), with DXS15 (Z = 3.737, theta = 0.00), with DXS52 (Z = 2.709, theta = 0.00), and with F8C (Z = 1.020, theta = 0.00). In the absence of any observable recombination, we are unable to sublocalise the XLMTM locus further within the Xq28 region. This evidence for an Xq28 localisation may allow us to carry out useful genetic counselling within such families.
PMCID: PMC1017076  PMID: 2352256
11.  Clinical and Pathological Features of Korean Patients with DNM2-Related Centronuclear Myopathy 
Background and Purpose
Centronuclear myopathy (CNM) is characterized by the presence of central nuclei within a large number of muscle fibers. Mutations of the dynamin 2 gene (DNM2) are common causes of autosomal dominant or sporadic CNM. The aim of this study was to characterize the clinical and pathological features of CNM relative to the presence of DNM2 mutations.
Six patients with clinical and pathological features of CNM were recruited. Detailed clinical and pathological findings were analyzed according to the presence of DNM2 mutations.
We detected DNM2 mutations in four of the six sporadic CNM patients, and identified the following distinct clinical and pathological features in those patients with DNM2 mutations: preferential involvement of the distal lower limbs, typical nuclear centralization, and radially distributed sarcoplasmic strands in muscle pathology. In contrast, those without DNM2 mutations exhibited rather diffuse muscular involvement, and nuclear internalization and myofibrillar disorganization were more pronounced features of their muscle pathology.
These findings suggest the presence of specific features in Korean CNM patients. A detailed clinical and pathological examination of CNM patients would be helpful for molecular genetic analyses of this condition.
PMCID: PMC3896645  PMID: 24465259
centronuclear myopathy; DNM2; muscle involvement; central nuclei; internal nuclei; sarcoplasmic strands
12.  Centronuclear (myotubular) myopathy 
Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.
The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.
The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.
Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.
Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.
The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.
Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.
PMCID: PMC2572588  PMID: 18817572
13.  Common Membrane Trafficking Defects of Disease Associated Dynamin 2 Mutations 
Traffic (Copenhagen, Denmark)  2011;12(11):1620-1633.
Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, Centronuclear Myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cellular defects that cause disease remain unclear, they are expected to be mild. To gain new insight into potential pathogenic mechanisms we utilized mouse Dyn2 conditional knock-out cells combined with retroviral-mediated reconstitution to mimic both heterozygous and homozygous states and characterized cellular phenotypes using quantitative assays for several membrane trafficking events. Surprisingly, none of the four mutants studied exhibited a defect in CME, but all were impaired in their ability to support p75/neurotrophin receptor export from the Golgi, the raft-dependent endocytosis of cholera toxin, and clathrin-independent endocytosis of EGFR. While it will be important to study these mutants in disease-relevant muscle and neuronal cells, given the importance of neurotrophic factors and lipid rafts in muscle physiology, we speculate that these common cellular defects might contribute to the tissue-specific diseases caused by a ubiquitously expressed protein.
PMCID: PMC3188678  PMID: 21762456
Charcot-Marie-Tooth disease; Centronuclear Myopathy; Clathrin-mediated endocytosis; EGF receptor; p75/neurotrophin receptor; lipid rafts
14.  Functionalized carbon nanomaterials: exploring the interactions with Caco-2 cells for potential oral drug delivery 
Although carbon nanomaterials (CNMs) have been increasingly studied for their biomedical applications, there is limited research on these novel materials for oral drug delivery. As such, this study aimed to explore the potential of CNMs in oral drug delivery, and the objectives were to evaluate CNM cytotoxicity and their abilities to modulate paracellular transport and the P-glycoprotein (P-gp) efflux pump. Three types of functionalized CNMs were studied, including polyhydroxy small-gap fullerenes (OH-fullerenes), carboxylic acid functionalized single-walled carbon nanotubes (f SWCNT-COOH) and poly(ethylene glycol) functionalized single-walled carbon nanotubes (f SWCNT-PEG), using the well-established Caco-2 cell monolayer to represent the intestinal epithelium. All three CNMs had minimum cytotoxicity on Caco-2 cells, as demonstrated through lactose dehydrogenase release and 3-(4,5-dimethyliazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Of the three CNMs, f SWCNT-COOH significantly reduced transepithelial electrical resistance and enhanced transport of Lucifer Yellow across the Caco-2 monolayer. Confocal fluorescence microscopy showed that f SWCNT-COOH treated cells had the highest perturbation in the distribution of ZO-1, a protein marker of tight junction, suggesting that f SWCNT-COOH could enhance paracellular permeability via disruption of tight junctions. This modulating effect of f SWCNT-COOH can be reversed over time. Furthermore, cellular accumulation of the P-gp substrate, rhodamine-123, was significantly increased in cells treated with f SWCNT-COOH, suggestive of P-gp inhibition. Of note, f SWCNT-PEG could increase rhodamine-123 accumulation without modifying the tight junction. Collectively, these results suggest that the functionalized CNMs could be useful as modulators for oral drug delivery, and the differential effects on the intestinal epithelium imparted by different types of CNMs would create unique opportunities for drug-specific oral delivery applications.
Video abstract
PMCID: PMC3215338  PMID: 22125408
fullerenes; carbon nanotubes; functionalization; paracellular transport; P-glycoprotein
15.  Autosomal Dominant Centronuclear Myopathy with Unique Clinical Presentations 
Journal of Korean Medical Science  2007;22(6):1098-1101.
Centronuclear myopathies are clinically and genetically heterogenous diseases with common histological findings, namely, centrally located nuclei in muscle fibers with a predominance and hypotrophy of type 1 fibers. We describe two cases from one family with autosomal dominant centronuclear myopathy with unusual clinical features that had initially suggested distal myopathy. Clinically, the patients presented with muscle weakness and atrophy localized mainly to the posterior compartment of the distal lower extremities. Magnetic resonance imaging revealed predominant atrophy and fatty changes of bilateral gastrocnemius and soleus muscles. This report demonstrates the expanding clinical heterogeneity of autosomal dominant centronuclear myopathy.
PMCID: PMC2694645  PMID: 18162732
Myopathies, Structural, Congenital; Autosomal Dominant Inheritance; Distal Myopathies
16.  Centronuclear myopathy related to dynamin 2 mutations: Clinical, morphological, muscle imaging and genetic features of an Italian cohort 
Neuromuscular Disorders  2013;23(3):229-238.
Mutations in dynamin 2 (DNM2) gene cause autosomal dominant centronuclear myopathy and occur in around 50% of patients with centronuclear myopathy. We report clinical, morphological, muscle imaging and genetic data of 10 unrelated Italian patients with centronuclear myopathy related to DNM2 mutations. Our results confirm the clinical heterogeneity of this disease, underlining some peculiar clinical features, such as severe pulmonary impairment and jaw contracture that should be considered in the clinical follow-up of these patients. Muscle MRI showed a distinct pattern of involvement, with predominant involvement of soleus and tibialis anterior in the lower leg muscles, followed by hamstring muscles and adductor magnus at thigh level and gluteus maximus. The detection of three novel DNM2 mutations and the first case of somatic mosaicism further expand the genetic spectrum of the disease.
PMCID: PMC3594745  PMID: 23394783
DNM2; Centronuclear myopathy; Muscle MRI; ‘Necklace’ fibers; Somatic mosaicism
17.  Linkage analysis of neurofibromatosis (von Recklinghausen disease). 
Journal of Medical Genetics  1983;20(5):334-337.
Linkage analysis of 28 genetic markers was undertaken in 108 subjects from 11 families with well-documented, classic, peripheral neurofibromatosis. Fifty-four persons were affected in one four-generation family, seven three-generation families, and three two-generation families. Lod scores were calculated using the standard LIPED programme for 49 combinations of theta male and theta female from 0.01 to 0.50. Lod scores excluded close linkage with 16 markers, including most tested on chromosome 1 and HLA on chromosome 6, and were inconclusive for 12 markers, including the secretor locus, closely linked to myotonic dystrophy. Analysis of five informative families resulted in a lod score of +2.2 for close linkage with GC on chromosome 4. However, the lod score for GC in the one additional informative family was negative, so that the final interpolated maximum was Z = 0.89 for theta male = 0.03, theta female = 0.28. Further studies are needed to evaluate this suggestion of linkage and possible genetic heterogeneity.
PMCID: PMC1049144  PMID: 6417334
18.  Retinitis pigmentosa families showing apparent X linked inheritance but unlinked to the RP2 or RP3 loci. 
Journal of Medical Genetics  1994;31(11):848-852.
Three families with retinitis pigmentosa (RP) are described in which the disorder shows apparent X linked inheritance but does not show linkage to the RP2 and RP3 regions of the short arm of the X chromosome. The families are also inconsistent with a localisation of the disease gene between DXS164 and DXS28. In one case, reassessment of the family in the light of these results suggested that the family may have an autosomal dominant form of RP. The remaining two families are consistent with X linkage and suggest the possibility of a new X linked RP (XLRP) locus. These families highlight the difficulties in determining the mode of inheritance on the basis of pedigree structure and clinical data alone. Molecular genetics plays an important role in confirming the mode of inheritance and in detecting potential misclassifications, particularly in a group of disorders as heterogeneous as RP. They emphasise that caution is required in genetic counselling of RP families, particularly in the absence of any molecular genetic analysis.
PMCID: PMC1016657  PMID: 7853368
19.  Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. 
Journal of Medical Genetics  1992;29(4):236-238.
Genetic linkage between atopic IgE responses and chromosome 11q13 (D11S97) has been previously reported in a limited number of extended families. Difficulties of phenotyping in the older family members, poor family structure in some families, and genetic heterogeneity were proposed as possible explanations for the variability in lod scores. To test this finding a second linkage study of 64 young nuclear families was undertaken and gave a two point lod score of 3.8 at theta = 0.07 (assuming theta m = theta f). A test of genetic heterogeneity in the nuclear families shows that atopic IgE responses are linked to this locus in 60 to 100% of families (approximate 95% confidence limits).
PMCID: PMC1015920  PMID: 1583642
20.  Linkage analysis of X linked retinitis pigmentosa in the Irish population. 
Journal of Medical Genetics  1988;25(4):222-226.
There is significant evidence for genetic and phenotypic heterogeneity in X linked retinitis pigmentosa (XLRP). We have studied the linkage of XLRP in four Irish families to a number of polymorphic DNA markers. We report linkage between the DXS7 (L1.28) locus and the XLRP locus (Z = 3.445, theta = 0.00). Combined with the previously published data on British and Danish families, the genetic distance between the DXS7 and XLRP loci is now estimated at 5 cM with a maximum lod score of 13.026 and a 1-lod confidence interval of 0.75 to 9.5 cM. Linkage was also observed between 754 and XLRP (Z = 3.41, theta = 0.00) and between pERT87 and XLRP (Z = 1.37, theta = 0.1). The heterogeneity of XLRP is discussed in relation to these observations.
PMCID: PMC1015500  PMID: 3163380
21.  Clinical and molecular genetic characterisation of a family segregating autosomal dominant retinitis pigmentosa and sensorineural deafness 
AIMS/BACKGROUND—To characterise clinically a large kindred segregating retinitis pigmentosa and sensorineural hearing impairment in an autosomal dominant pattern and perform genetic linkage studies in this family. Extensive linkage analysis in this family had previously excluded the majority of loci shown to be involved in the aetiologies of RP, some other forms of inherited retinal degeneration, and inherited deafness.
METHODS—Members of the family were subjected to detailed ophthalmic and audiological assessment. In addition, some family members underwent skeletal muscle biopsy, electromyography, and electrocardiography. Linkage analysis using anonymous microsatellite markers was performed on DNA samples from all living members of the pedigree.
RESULTS—Patients in this kindred have a retinopathy typical of retinitis pigmentosa in addition to a hearing impairment. Those members of the pedigree examined demonstrated a subclinical myopathy, as evidenced by abnormal skeletal muscle histology, electromyography, and electrocardiography. LOD scores of Zmax = 3. 75 (Θ = 0. 10), Zmax = 3. 41 (Θ = 0. 10), and Zmax = 3. 25 (Θ = 0. 15) respectively were obtained with the markers D9S118, D9S121, and ASS, located on chromosome 9q34-qter, suggesting that the causative gene in this family may lie on the long arm (q) of chromosome 9.
CONCLUSIONS—These data indicate that the gene responsible for the phenotype in this kindred is located on chromosome 9q. These data, together with evidence that a murine deafness gene is located in a syntenic area of the mouse genome, should direct the research community to consider this area as a candidate region for retinopathy and/or deafness genes.

PMCID: PMC1722127  PMID: 9135384
22.  Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree 
BACKGROUND/AIMS—Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases. A large autosomal dominant FEVR family was studied, both clinically and by linkage analysis, to determine whether it differed from the known forms of FEVR.
METHODS—Affected members and obligate gene carriers from this family were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and in some cases fluorescein angiography. Patient DNAs were genotyped for markers at the EVR1 locus on chromosome 11q13.
RESULTS—The clinical evaluation in this family is consistent with previous descriptions of FEVR pedigrees, but linkage analysis proves that it has a form of FEVR genetically distinct from the EVR1 locus on 11q.
CONCLUSION—This proves that there are at least three different loci associated with comparable FEVR phenotypes, a situation similar to that existing for many forms of retinal degeneration.

PMCID: PMC1723437  PMID: 10729291
23.  Analysis of alcohol dependence phenotype in the COGA families using covariates to detect linkage 
BMC Genetics  2005;6(Suppl 1):S143.
Linkage analysis methods that incorporate etiological heterogeneity of complex diseases are likely to demonstrate greater power than traditional linkage analysis methods. Several such methods use covariates to discriminate between linked and unlinked pedigrees with respect to a certain disease locus. Here we apply several such methods including two mixture models, ordered subset analysis, and a conditional logistic model to genome scan data on the DSM-IV alcohol dependence phenotype on the Collaborative Studies on Genetics of Alcoholism families, and compare the results to traditional nonparametric linkage analysis. In general, there was little agreement among the various covariate-based linkage statistics. Linkage signals with empirical p-values less than 0.001 were detected on chromosomes 3, 4, 7, 10, and 12, with the highest peak occurring at the GABRB1 gene using the ecb21 covariate.
PMCID: PMC1866792  PMID: 16451603
24.  X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. 
Journal of Medical Genetics  1993;30(5):381-384.
X linked hereditary spastic paraplegia is a rare condition that has been divided into two forms (the pure spastic form and the complicated form) as a function of clinical course and severity. A gene for pure hereditary spastic paraplegia (SPG2) has been mapped to the proximal long arm of the X chromosome (Xq21) by linkage to the DXS17 locus, while a gene for a complicated form of the disease has been mapped to the distal long arm by linkage to the DXS52 locus (Xq28). Here we report on the mapping of a gene for complicated hereditary spastic paraplegia to the Xq21 region by linkage to the probe S9 at the DXS17 locus (Z = 5 at theta = 0.04) in a three generation pedigree. Multipoint linkage analysis supports the distal location of the disease gene with respect to the DXYS1-DXS17 block (cen-DXYS1-DXS3-DXS17-SPG2-tel). The observation of a complicated form of spastic paraplegia mapping to Xq21 raises the difficult issue of variable phenotypic expression, allelic heterogeneity, or even close proximity of two genes for hereditary spastic paraplegia in this region. However, since our study provides clinical evidence for intrafamilial heterogeneity in complicated X linked spastic paraplegia, the present data support the hypothesis of variable clinical expression of a single gene at the SPG2 locus, as previously suggested for SPG1. Finally, we report here what we believe to be the first evidence of clinical expression in heterozygous carriers, a feature that is relevant to genetic counselling in at risk females.
PMCID: PMC1016372  PMID: 8320699
25.  Emery-Dreifuss muscular dystrophy: linkage to markers in distal Xq28. 
Journal of Medical Genetics  1993;30(2):108-111.
Emery-Dreifuss muscular dystrophy (EMD) is characterised by (1) early contractures of the Achilles tendons, elbows, and postcervical muscles, (2) slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution in the early stages, and (3) cardiomyopathy with conduction defects and risk of sudden death. Inheritance is usually X linked recessive but can be autosomal dominant. Family linkage studies have mapped X linked EMD to the distal long arm of the X chromosome but precise genetic localisation has been hampered by the rarity of this condition. We report three new families with X linked Emery-Dreifuss muscular dystrophy studied with DNA markers from Xq27-qter and three previously published families typed for additional markers. No recombination was observed with the red/green cone pigment locus, RGCP (lod score, Z = 2.46), the factor VIII coagulant gene locus, F8C (Z = 6.39), or with DXS115 (Z = 4.94). Two recombinants were observed which mapped EMD distal to DXS15 (DX13) and DXS52 (St14) respectively. Multipoint linkage analysis gave odds exceeding 200:1 for EMD being distal to these markers. A multipoint analysis incorporating published data gave the map cen-DXS304-9cM-DXS15-3cM-DXS52-2 cM-(RGCP,EMD)-3cM-F8C-2cM-DXS115 with odds of 120:1 in favour of a location for EMD between DXS52 and F8C as compared to the next best position distal to F8C.
PMCID: PMC1016264  PMID: 8445613

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