Journal article
Uniparental disomy unveils a novel recessive mutation in POMT2
Neuromuscular disorders : NMD, Vol.28(7), pp.592-596
07/2018
DOI: 10.1016/j.nmd.2018.04.003
PMCID: PMC6115279
PMID: 29759639
Abstract
•A novel c.1502A>C mutation in POMT2 causes limb girdle muscular dystrophy.•This mutation leads to abnormal functional glycosylation of α-dystroglycan.•Uniparental disomy is manifested by a 15 Mb region of homozygosity on chromosome 14.•The POMT2 locus is within the region of homozygosity on chromosome 14.•The maternal recessive POMT2 mutation is unmasked by uniparental disomy.
Mutations in POMT2 are most commonly associated with Walker–Warburg syndrome and Muscle-Eye-Brain disease, but can also cause limb girdle muscular dystrophy (LGMD2N). We report a case of LGMD due to a novel mutation in POMT2 unmasked by uniparental isodisomy. The patient experienced proximal muscle weakness from three years of age with minimal progression. She developed progressive contractures and underwent unilateral Achilles tenotomy. By age 11, she had borderline low left ventricular ejection fraction and mild restrictive lung disease. Muscle biopsy showed mild dystrophic changes with selective reduction in α-dystroglycan immunostaining. Sequencing of POMT2 showed a novel homozygous c.1502A>C variant that was predicted to be probably pathogenic. Fibroblast complementation studies showed lack of functional glycosylation rescued by wild-type POMT2 expression. Chromosomal microarray showed a single 15 Mb copy number neutral loss of heterozygosity on chromosome 14 encompassing POMT2. RNAseq verified homozygosity at this locus. Together, our findings indicate maternal uniparental isodisomy causing LGMD2N.
Details
- Title: Subtitle
- Uniparental disomy unveils a novel recessive mutation in POMT2
- Creators
- Brianna N Brun - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USATobias Willer - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USABenjamin W Darbro - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAHernan D Gonorazky - Division of Neurology, Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, CanadaSergey Naumenko - Centre for Computational Medicine, Hospital for Sick Children, Toronto, CanadaJames J Dowling - Division of Neurology, Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, CanadaKevin P Campbell - Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USASteven A Moore - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAKatherine D Mathews - Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Neuromuscular disorders : NMD, Vol.28(7), pp.592-596
- DOI
- 10.1016/j.nmd.2018.04.003
- PMID
- 29759639
- PMCID
- PMC6115279
- NLM abbreviation
- Neuromuscul Disord
- ISSN
- 0960-8966
- eISSN
- 1873-2364
- Publisher
- Elsevier B.V
- Grant note
- name: Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, award: U54 NS053672; DOI: 10.13039/100008762, name: Genome Canada
- Language
- English
- Date published
- 07/2018
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Medical Genetics and Genomics; Neurology (Pediatrics)
- Record Identifier
- 9984047996702771
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