A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in<i>MYO18B</i>

Alazami, Anas M.; Kentab, Amal Y.; Faqeih, Eissa; Mohamed, Jawahir Y.; Alkhalidi, Hisham; Hijazi, Hadia; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2014-102964

Cited by 68 publications

(62 citation statements)

References 17 publications

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“…Seven genes harbored ≥ 2 variants of which only two (CWF19L1 and MYO18B) harbored two variants predicted to be damaging according to SIFT (score o0.05) and Polyphen2 (score 40.85) or resulted in a premature stop codon. MYO18B is unlikely to cause ARCA as variants in this gene are associated with lung cancer 9 or linked to Klippel-Feil anomaly and myopathy, 10 which were not present in our patient. However, during the course of our studies, CWF19L1 was reported as a novel cause of ARCA 3 and we focused further on this gene.…”

Section: Resultsmentioning

confidence: 55%

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

et al. 2015

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Autosomal recessive cerebellar ataxia (ARCA) is a group of neurological disorders characterized by degeneration or abnormal development of the cerebellum and spinal cord. ARCA is clinically and genetically highly heterogeneous, with over 20 genes involved. Exome sequencing of a girl with ARCA from non-consanguineous Dutch parents revealed two pathogenic variants c.37G4C; p.D13H and c.946A4T; p.K316* in CWF19L1, a gene with an unknown function, recently reported to cause ARCA in a Turkish family. Sanger sequencing showed that the c.37G4C variant was inherited from the father and the c.946A4T variant from the mother. Pathogenicity was based on the damaging effect on protein function as the c.37G4C variant changed the highly conserved, negatively charged aspartic acid to the positively charged histidine and the c.946A4T variant introduced a premature stop codon. In addition, 27 patients with ARCA were tested for pathogenic variants in CWF19L1, however, no pathogenic variants were identified. Our data confirm CWF19L1 as a novel but rare gene causing ARCA. European Journal of Human Genetics (2016) 24, 619-622; doi:10.1038/ejhg.2015.158; published online 22 July 2015 INTRODUCTIONAutosomal recessive cerebellar ataxia (ARCA) is a group of rare, genetically and clinically heterogeneous neurological disorders affecting both the peripheral and central nervous systems, mainly occurring in children and young adults. 1 Clinical manifestations range from progressive cerebellar syndromes, as a key feature, to spinocerebellar symptoms with spasticity, ophthalmoplegia, sensory/motor neuropathy, involuntary movements, seizures, cognitive impairment, skeletal abnormalities and cutaneous disorders. To date, more than 20 genes have been reported to cause ARCA, however, explaining only 40% of cases. 2 Recently, pathogenic variants were described in a novel gene (CWF19L1) in two siblings with autosomal recessive ataxia syndrome. 3 Here, we report a second case, a girl from non-consanguineous Dutch parents, with cerebellar ataxia and atrophy, who was compound heterozygous for pathogenic variants in the CWF19L1 gene. Our results confirm the suggested role of CWF19L1 in rare cases of autosomal recessive cerebellar ataxia.

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Section: Resultsmentioning

confidence: 55%

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

et al. 2015

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“…The recent identification of MYO18B mutations in patients exhibiting symptoms of nemaline myopathy has, however, provided circumstantial evidence for a role of MYO18B in skeletal myogenesis; consistent with this, muscle biopsy analyses revealed defects in sarcomeric organization (Alazami et al 2015;Malfatti et al 2015) reminiscent of those seen in the cardiomyocytes of Myo18B mutant mice (Ajima et al 2008).…”

Section: Discussionmentioning

confidence: 86%

“…In the first of these, two patients with Klippel-Feil anomaly (KFA) were found to be homozygous for a nonsense mutation in the penultimate exon of the MYO18B gene (Alazami et al 2015); notably, both patients exhibited symptoms of myopathy (hypotonia and muscle weakness), a condition not previously associated with KFA. Muscle biopsy analysis of one patient revealed variation in fiber size and a loss of normal banding indicative of a loss of thick filaments.…”

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confidence: 99%

A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B

et al. 2017

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Myosin 18B is an unconventional myosin that has been implicated in tumor progression in humans. In addition, loss-offunction mutations of the MYO18B gene have recently been identified in several patients exhibiting symptoms of nemaline myopathy. In mouse, mutation of Myo18B results in early developmental arrest associated with cardiomyopathy, precluding analysis of its effects on skeletal muscle development. The zebrafish, frozen (fro) mutant was identified as one of a group of immotile mutants in the 1996 Tübingen genetic screen. Mutant embryos display a loss of birefringency in their skeletal muscle, indicative of disrupted sarcomeric organization. Using meiotic mapping, we localized the fro locus to the previously unannotated zebrafish myo18b gene, the product of which shares close to 50% identity with its human ortholog. Transcription of myo18b is restricted to fast-twitch myocytes in the zebrafish embryo; consistent with this, fro mutant embryos exhibit defects specifically in their fast-twitch skeletal muscles. We show that sarcomeric assembly is blocked at an early stage in fro mutants, leading to the disorganized accumulation of actin, myosin, and a-actinin and a complete loss of myofibrillar organization in fast-twitch muscles.

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“…A list of known genes (Supplemental Table 1) was constructed from multiple online database resources (http:// www.omim.org/, http://www.mnglabs.com/tests/, http://www. ncbi.nlm.nih.gov/pubmed) or abstracted from recently published articles (2,3,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Deleterious variants in the known arthrogryposis-associated genes were identified in 17 of 48 (35.4%) unrelated families (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

111

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A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation inMYO18B

Abstract: Deficiency of MYO18B is linked to a novel developmental disorder which combines KFA with myopathy. This suggests a widespread developmental role for this gene in humans, as observed for its murine ortholog.

Cited by 68 publications

References 17 publications

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

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