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1.  RYR1 mutations cause ophthalmoplegia, facial weakness, and malignant hyperthermia 
JAMA ophthalmology  2013;131(12):10.1001/jamaophthalmol.2013.4392.
To determine the genetic cause of congenital ptosis, ophthalmoplegia, facial paralysis and mild hypotonia segregating in two pedigrees diagnosed with atypical Moebius syndrome or congenital fibrosis of the extraocular muscles (CFEOM).
Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed.
Missense mutations resulting in two homozygous RYR1 amino acid substitutions (E989G and R3772W) and two compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in a consanguineous and a non-consanguineous pedigree, respectively. Orbital magnetic resonance imaging (MRI) revealed marked hypoplasia of extraocular muscles and intraorbital cranial nerves. Skeletal muscle biopsies revealed non-specific myopathic changes. Clinically, the patients’ ophthalmoplegia and facial weakness were far more significant than their hypotonia and limb weakness, and were accompanied by an unrecognized susceptibility to malignant hyperthermia.
Affected children presenting with severe congenital ophthalmoplegia and facial weakness in the setting of only mild skeletal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were susceptible to malignant hyperthermia. While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical because they lacked significant weakness, respiratory insufficiency, or scoliosis.
Clinical relevance
RYR1-associated myopathies should be included in the differential diagnosis of congenital ophthalmoplegia and facial weakness, even without clinical skeletal myopathy. These patients should also be considered susceptible to malignant hyperthermia, a life-threatening anesthetic complication avoidable if anticipated pre-surgically.
PMCID: PMC3865174  PMID: 24091937
2.  Complex cytogenetic rearrangements at the DURS1 locus in syndromic Duane retraction syndrome 
Clinical case reports  2013;1(1):10.1002/ccr3.11.
PMCID: PMC3885256  PMID: 24416505
Duane retraction syndrome; DURS1; 8q12 microduplication syndrome; cytogenetics; copy number variation
3.  Pontine malformation, undecussated pyramidal tracts and regional polymicrogyria: a new syndrome 
Pediatric neurology  2013;50(4):384-388.
Horizontal gaze palsy and progressive scoliosis (HGPPS) is caused by mutations in the ROBO3 gene, which plays a role in axonal guidance during brain development. HGPPS is characterized by the congenital absence of conjugate lateral eye movements with preserved vertical gaze and progressive scoliosis, as well as dysgenesis of brainstem structures and ipsilateral projection of the pyramidal tract.
A 4-year-11-month-old girl presented with psychomotor retardation and autistic traits. Magnetic resonance imaging revealed hypoplasia and malformation of the ventral portion of the pons and medulla oblongata. Diffusion tensor imaging revealed the absence of decussation of the bilateral pyramidal tracts. These findings were similar to the typical findings for HGPPS. However, restriction of horizontal eye movement was minimal, and bilateral polymicrogyria were also noted in the occipitotemporal cortex in the present patient. These findings have not been previously reported in patients with HGPPS. No mutations in the ROBO3, SLIT1, SLIT2, NTN1, SEMA3A and SEMA3F genes were identified.
This patient may have a disorder caused by an unidentified factor, other than a mutation in the genes analyzed, involved in corticogenesis, axonal guidance, and brainstem morphogenesis.
PMCID: PMC3959267  PMID: 24507697
pontine malformation; brainstem hypoplasia; polymicrogyria; axonal guidance; decussation of the pyramidal tract; horizontal gaze palsy and progressive scoliosis
4.  A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3 
Brain  2013;136(2):522-535.
Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein β-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site. We report the detailed phenotypes of eight unrelated individuals who harbour this de novo mutation, and thus define the ‘TUBB3 E410K syndrome’. Individuals harbouring this mutation were previously reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay and possible peripheral neuropathy. We now confirm by electrophysiology that a progressive sensorimotor polyneuropathy does indeed segregate with the mutation, and expand the TUBB3 E410K phenotype to include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), stereotyped midface hypoplasia, intellectual disabilities and, in some cases, vocal cord paralysis, tracheomalacia and cyclic vomiting. Neuroimaging reveals a thin corpus callosum and anterior commissure, and hypoplastic to absent olfactory sulci, olfactory bulbs and oculomotor and facial nerves, which support underlying abnormalities in axon guidance and maintenance. Thus, the E410K substitution defines a new genetic aetiology for Moebius syndrome, Kallmann syndrome and cyclic vomiting. Moreover, the c.1228G>A mutation was absent in DNA from ∼600 individuals who had either Kallmann syndrome or isolated or syndromic ocular and/or facial dysmotility disorders, but who did not have the combined features of the TUBB3 E410K syndrome, highlighting the specificity of this phenotype–genotype correlation. The definition of the TUBB3 E410K syndrome will allow clinicians to identify affected individuals and predict the mutation based on clinical features alone.
PMCID: PMC3572929  PMID: 23378218
Kallmann syndrome; cyclic vomiting; peripheral neuropathy; CFEOM; TUBB3
5.  An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation 
Human Molecular Genetics  2012;21(26):5484-5499.
Microtubules are essential components of axon guidance machinery. Among β-tubulin mutations, only those in TUBB3 have been shown to cause primary errors in axon guidance. All identified mutations in TUBB2B result in polymicrogyria, but it remains unclear whether TUBB2B mutations can cause axon dysinnervation as a primary phenotype. We have identified a novel inherited heterozygous missense mutation in TUBB2B that results in an E421K amino acid substitution in a family who segregates congenital fibrosis of the extraocular muscles (CFEOM) with polymicrogyria. Diffusion tensor imaging of brains of affected family members reveals aberrations in the trajectories of commissural projection neurons, implying a paucity of homotopic connections. These observations led us to ask whether axon dysinnervation is a primary phenotype, and why the E421K, but not other, TUBB2B substitutions cause CFEOM. Expression of exogenous Tubb2b-E421K in developing callosal projection neurons is sufficient to perturb homotopic connectivity, without affecting neuronal production or migration. Using in vitro biochemical assays and yeast genetics, we find that TUBB2B-E421K αβ-heterodimers are incorporated into the microtubule network where they alter microtubule dynamics and can reduce kinesin localization. These data provide evidence that TUBB2B mutations can cause primary axon dysinnervation. Interestingly, by incorporating into microtubules and altering their dynamic properties, the E421K substitution behaves differently than previously identified TUBB2B substitutions, providing mechanistic insight into the divergence between resulting phenotypes. Together with previous studies, these findings highlight that β-tubulin isotypes function in both conserved and divergent ways to support proper human nervous system development.
PMCID: PMC3516133  PMID: 23001566
6.  Complex cytogenetic rearrangements at the DURS1 locus in syndromic Duane retraction syndrome 
Clinical Case Reports  2013;1(1):30-37.
Key Clinical Message
A patient with syndromic Duane retraction syndrome harbors a chromosome 811.1q13.2 inversion and 8p11.1-q12.3 marker chromosome containing subregions with differing mosaicism and allele frequencies. This case highlights the potential requirement for multiple genetic methods to gain insight into genotype–phenotype correlation, and ultimately into molecular mechanisms that underlie human disease.
PMCID: PMC3885256  PMID: 24416505
8q12 microduplication syndrome; copy number variation; cytogenetics; Duane retraction syndrome; DURS1
7.  Two novel CHN1 mutations in two families with Duane’s retraction syndrome 
Archives of ophthalmology  2011;129(5):649-652.
To determine the genetic cause of Duane’s retraction syndrome (DRS) in two families segregating DRS as an autosomal dominant trait.
Members of two unrelated pedigrees were enrolled in an ongoing genetic study. Linkage analysis was performed using fluorescent microsatellite markers flanking the CHN1 locus. Probands and family members were screened for CHN1 mutations.
Of the six clinically affected individuals in the two pedigrees, three have bilateral and three have unilateral DRS. Both pedigrees are consistent with linkage to the DURS2 locus, one with complete and one with incomplete penetrance. Sequence analysis revealed the pedigrees segregate novel heterozygous missense CHN1 mutations, c.422C>T and c.754C>T, predicted to result in α2-chimaerin amino acid substitutions P141L and P252S, respectively.
Genetic analysis of two pedigrees segregating nonsyndromic DRS reveals two novel mutations in CHN1, bringing the number of DRS pedigrees know to harbor CHN1 mutations, and the number of unique CHN1 mutations, from seven to nine. Both mutations identified in this study alter residues that participate in intramolecular interactions that stabilize the inactive, closed conformation of α2-chimerin, and thus are predicted to result in its hyper-activation. Moreover, amino acid residue P252 was altered to a different residue in a previously reported DRS pedigree; thus, this is the first report of two CHN1 mutations altering the same residue, further supporting a gain-of-function etiology.
Clinical Relevance
Members of families segregating DRS as an autosomal dominant trait should be screened for mutations in the CHN1 gene, enhancing genetic counseling and permitting earlier diagnosis.
PMCID: PMC3517173  PMID: 21555619
8.  Expansion of the CHN1 Strabismus Phenotype 
Hyperactivating mutations in the CHN1 gene can cause supraduction deficits in the absence of Duane retraction syndrome.
Hyperactivating CHN1 mutations have been described in individuals with Duane retraction syndrome with or without vertical gaze abnormalities. This was a study of five family members with distinctive ocular dysmotility patterns that co-segregated with a novel hyperactivating CHN1 mutation.
Participating members of a family segregating pleomorphic incomitant strabismus underwent ophthalmic examinations, and several underwent high-resolution magnetic resonance imaging (MRI) of the orbits and brain stem. Participant DNA was extracted and amplified for haplotype analysis encompassing the CHN1 region on chromosome 2q31.1, and mutation analysis of the CHN1 gene, which encodes the Rac-GAP signaling protein α2-chimaerin. In vitro functional studies of the co-inherited mutation were performed, including a Rac-GTP activation assay, quantification of α2-chimaerin translocation, and co-immunoprecipitation.
All five clinically affected family members exhibited monocular or binocular supraduction deficits, three in the absence of Duane retraction syndrome. MRI in four affected individuals demonstrated small or absent abducens nerves in all four, small oculomotor nerve in one, and small optic nerves in three. Superior oblique muscle volume was also decreased in three of the individuals, supporting trochlear nerve hypoplasia. Strabismus segregated with the CHN1 locus and affected individuals harbored a c.443A>T CHN1 mutation (p.Y148F). In vitro, this novel mutation behaved similarly to previously reported CHN1 mutations underlying familial Duane syndrome, hyperactivating α2-chimaerin by enhancing its dimerization and membrane association and lowering total intracellular Rac-GTP.
Analysis of the current pedigree expands the phenotypic spectrum of hyperactivating CHN1 mutations to include vertical strabismus and supraduction deficits in the absence of Duane retraction syndrome.
PMCID: PMC3175992  PMID: 21715346
9.  Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance 
Cell  2010;140(1):74-87.
We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific β-tubulin isotype III, result in a spectrum of human nervous system disorders we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves, and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate normal TUBB3 is required for axon guidance and maintenance in mammals.
PMCID: PMC3164117  PMID: 20074521
10.  CHN1 Mutations are not a Common Cause of Sporadic Duane’s Retraction Syndrome 
PMCID: PMC2801889  PMID: 20034095
Duane; Duane retraction syndrome; congenital cranial dysinnervation disorder; CHN1; chimaerin
11.  Crystalline cataract caused by a heterozygous missense mutation in γD-crystallin (CRYGD) 
Molecular Vision  2011;17:3333-3338.
To describe phenotypic characteristics of two pedigrees manifesting early onset crystalline cataract with mutations in the γD-crystallin gene (CRYGD).
A detailed medical history was obtained from two Caucasian pedigrees manifesting autosomal dominant congenital cataracts. Genomic DNA was extracted from saliva (DNA Genotek). Single Nucleotide Polymorphism (SNP) based genome analysis of the larger pedigree revealed linkage to an 8.2 MB region on chromosome 2q33-q35 which encompassed the crystallin-gamma gene cluster (CRYG). Exons and flanking introns of CRYGA, CRYGB, CRYGC and CRYGD were amplified and sequenced to identify disease-causing mutations.
A morphologically unique cataract with extensive refractile “crystals” scattered throughout the nucleus and perinuclear cortex was found in the probands from both pedigrees. A heterozygous C→A mutation was identified at position 109 of the coding sequence (R36S of the processed protein) in exon 2 of CRYGD and this missense mutation was found to cosegregate with the disease in the larger family; this mutation was then identified in affected individuals of pedigree 2 as well.
The heterozygous 109C→A CRYGD missense mutation is associated with a distinct crystalline cataract in two US Caucasian pedigrees. This confirms crystalline cataract formation with this mutation, as previously reported in sporadic childhood case from the Czech Republic and in members of a Chinese family.
PMCID: PMC3247172  PMID: 22219628
12.  HOXA1 mutations are not a common cause of Möbius syndrome 
The HOXA1-related syndromes result from autosomal recessive truncating mutations in the homeobox transcription factor, HOXA1. Limited horizontal gaze and sensorineural deafness are the most common features; affected individuals can also have facial weakness, mental retardation, autism, motor disabilities, central hypoventilation, carotid artery and/or conotruncal heart defects. Möbius syndrome is also phenotypically heterogeneous, with minimal diagnostic criteria of nonprogressive facial weakness and impaired ocular abduction; mental retardation, autism, motor disabilities, additional eye movements restrictions, hearing loss, hypoventilation, and craniofacial, lingual, and limb abnormalities also occur. We asked, given the phenotypic overlap between these syndromes and the variable expressivity of both disorders, whether individuals with Möbius syndrome might harbor mutations in HOXA1. Our results suggest that HOXA1 mutations are not a common cause of sporadic Möbius syndrome in the general population.
PMCID: PMC2862693  PMID: 20227628
13.  Two pedigrees segregating Duane’s retraction syndrome as a dominant trait map to the DURS2 genetic locus 
To determine the molecular etiologies of Duane’s retraction syndrome (DRS), we are investigating its genetic bases. We have previously identified the transcription factors SALL4 and HOXA1 as the genes mutated in DRS with radial anomalies, and in DRS with deafness, vascular anomalies, and cognitive deficits, respectively. We know less, however, about the genetic etiology of DRS when it occurs in isolation, and only one genetic locus for isolated DRS, the DURS2 locus on chromosome 2, has been mapped to date. Toward the goal of identifying the DURS2 gene, we have ascertained and studied two pedigrees that segregate DRS as a dominant trait.
We enrolled members of two large dominant DRS pedigrees into our ongoing study of the genetic basis of the congenital cranial dysinnervation disorders, and conducted linkage analysis to determine if their DRS phenotype maps to the DURS2 locus.
By haplotype analysis, the DRS phenotype in each family co-segregates with markers spanning the DURS2 region, and linkage analysis reveals maximum lod scores of >2, establishing that the DRS phenotype in these two pedigrees maps to the DURS2 locus.
These two pedigrees double the published pedigrees known to map to the DURS2 locus, and can thus contribute toward the search for the DURS2 gene. The affected members represent a genetically defined population of DURS2-linked DRS individuals, and hence studies of their clinical and structural features can enhance our understanding of the DURS2 phenotype, as described in the companion paper.
PMCID: PMC2829295  PMID: 17197532
Duane’s syndrome; linkage analysis; DUR2
14.  KIF21A mutations in two Chinese families with congenital fibrosis of the extraocular muscles (CFEOM) 
Molecular Vision  2010;16:2062-2070.
Two Chinese families (XT and YT) with congenital fibrosis of the extraocular muscles (CFEOM) were identified. The purpose of this study was to determine if previously described Homo sapiens kinesin family member 21A (KIF21A) mutations were responsible for CFEOM in these two Chinese pedigrees.
Clinical characterization and genetic studies were performed. Microsatellite genotyping for linkage to the CFEOM1 and CFEOM3 loci was performed. The probands were screened for KIF21A mutations by bidirectional direct sequencing. Once a mutation was detected in the proband, all other participating family members and 100 unrelated control normal individuals were screened for the mutation.
All affected individuals in family XT shared the common manifestations of CFEOM1. Family YT had two affected individuals, a mother and a daughter. The daughter had CFEOM1, while her mother never had congential ptosis but did have limited extraocular movements status post strabismus surgery. Haplotype analysis revealed that pedigree XT was linked to the 12q CFEOM1 locus and the affected memberes harbored the second most common missense mutation in KIF21A (2,861G>A, R954Q). Family YT harbored the most common missense de novo mutation in KIF21A (2,860C>T, R954W). Both of these mutations have been previously described.
The observation of these two KIF21A mutations in a Chinese pedigree underscores the homogeneity of these mutations as a cause of CFEOM1 and CFEOM3 across ethnic divisions.
PMCID: PMC2965570  PMID: 21042561
15.  Magnetic resonance imaging of the endophenotype of a novel familial Möbius-like syndrome 
Möbius’ syndrome typically presents as a sporadic trait with congenital facial palsy and abduction impairment. We used high resolution magnetic resonance imaging (MRI) and genetic analysis to examine a family with features of Möbius’ syndrome.
We examined three related family members having congenital complete opthalmoplegia with ptosis and facial diplegia. Orbits were imaged in quasi-coronal and sagittal planes 2 mm thick. Subarachnoid cranial nerves were imaged in planes 1 mm thick. Linkage and mutation analysis were performed to determine if the pedigree harbored mutations in four candidate genes.
In affected subjects, MRI showed marked hypoplasia of extraocular muscles and intraorbital motor nerves. In the anterior orbit, rectus extraocular muscles were less hypoplastic but markedly curved toward insertion. Oblique extraocular muscles were hypoplastic and abnormally inserted. Posterior bony orbits were hypoplastic. Optic nerves were markedly straightened. Brainstems and cranial nerves III, VI, VII, and VIII were normal bilaterally. No pathogenic mutations were detected in affected individuals.
Previous MRI studies have demonstrated brainstem hypoplasia and cranial nerve aplasia in Möbius’ syndrome. The current family had normal brainstems and subarachnoid portions of motor cranial nerves innervating the orbit, but marked extraocular muscle hypoplasia. These clinical and MRI findings are atypical for Möbius’ syndrome and other congenital cranial dysinnervation disorders (CCDDs). Congenital facial weakness and complete ophthalmoplegia may occur despite MRI evidence of normal brainstem anatomy. The endophenotype appears to result from a genetic defect distinct from the CCDDs defined thus far, rather than a global brainstem insult.
PMCID: PMC2562269  PMID: 18455936
16.  Human CHN1 mutations hyperactivate α2-chimaerin and cause Duane’s retraction syndrome 
Science (New York, N.Y.)  2008;321(5890):839-843.
The RacGAP molecule α2-chimaerin is implicated in neuronal signaling pathways required for precise guidance of developing corticospinal axons. We now demonstrate that a variant of Duane’s retraction syndrome, a congenital eye movement disorder in which affected individuals show aberrant development of axon projections to the extraocular muscles, can result from gain-of-function heterozygous missense mutations in CHN1 that increase α2-chimaerin RacGAP activity in vitro. A subset of mutations enhances α2-chimaerin membrane translocation and/or α2-chimaerin’s previously unrecognized ability to form a complex with itself. In ovo expression of mutant CHN1 alters the development of ocular motor axons. These data demonstrate that human CHN1 mutations can hyperactivate α2-chimaerin and result in aberrant cranial motor neuron development.
PMCID: PMC2593867  PMID: 18653847
18.  Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis 
Science (New York, N.Y.)  2004;304(5676):1509-1513.
The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing.
PMCID: PMC1618874  PMID: 15105459
19.  Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1 
BMC Genetics  2007;8:26.
Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A.
Sixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands.
Analysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.
PMCID: PMC1888713  PMID: 17511870

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