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Homozygous Mutations in VAMP1 Cause a Presynaptic Congenital

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Homozygous Mutations in VAMP1 Cause a Presynaptic Congenital View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery BRIEF COMMUNICATION Homozygous Mutations in can be implicated in CMS pathophysiology, including mutations in genes encoding proteins associated with the VAMP1 Cause a Presynaptic muscle nicotinic acetylcholine receptor and the synaptic basal lamina, or (more rarely) involved in the NMJ pre- Congenital Myasthenic 2–6 synaptic transmission. Syndrome We describe 2 families from Kuwait and Israel where 2 of the siblings in each family presented clinical 1* and neurophysiological features typical of a presynaptic Vincenzo Salpietro, MD, CMS. Whole exome sequencing (WES) or whole 2* Weichun Lin, PhD, genome sequencing (WGS) followed by Sanger sequenc- 3,4* Andrea Delle Vedove, MD, ing unraveled either a homozygous frameshift or missense 3,4 2 Markus Storbeck, PhD, Yun Liu, PhD, variants in VAMP1 segregating with the phenotype in the 1 Stephanie Efthymiou, MSc, 2 families. Screening a cohort of 63 undiagnosed CMS 1 Andreea Manole, BSc, individuals failed to show any further causative variant in 1 Sarah Wiethoff, MD, PhD, VAMP1. Qiaohong Ye, BSc,2 Anand Saggar, MD,5 6 Kenneth McElreavey, PhD, Materials and Methods Shyam S. Krishnakumar, PhD,7,8 Subjects SYNAPS Study Group, This study was approved by the institutional review boards of Matthew Pitt, MD,9 7,8 the participating centers. Informed consent was obtained from Oscar D. Bello, PhD, the families. Clinical details were obtained from medical James E. Rothman, PhD,7,8 From the 1Department of Molecular Neuroscience, Institute of Neurology, 10,11,12 Lina Basel-Vanagaite, MD, PhD, University College London Institute of Neurology, London, United Kingdom; 2 Monika Weisz Hubshman, MD, PhD,10,11,12 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX; 3Institute of Human Genetics, Center for Molecular 12,13 Sharon Aharoni, MD, Medicine Cologne, Cologne, Germany; 4Institute for Genetics, 5 Adnan Y. Manzur, MD,14 University of Cologne, Cologne, Germany; St George’s Hospital, National Health Service Foundation Trust, London, United Kingdom; 3 Brunhilde Wirth, PhD, and 6Human Developmental Genetics, Pasteur Institute, Paris, France; 7 Henry Houlden, MD, PhD1 Department of Cell Biology, Yale School of Medicine, New Haven, CT; 8Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, United Kingdom; 9Department We report 2 families with undiagnosed recessive pre- of Clinical Neurophysiology, Great Ormond Street Hospital for synaptic congenital myasthenic syndrome (CMS). Children, National Health Service Foundation Trust, London, United Kingdom; 10Pediatric Genetics Unit, Schneider Children’s Medical Whole exome or genome sequencing identified segre- 11 Center of Israel, Petach Tikva, Israel; Raphael Recanati Genetic gating homozygous variants in VAMP1: c.51_ Institute, Rabin Medical Center, Petach Tikva, Israel; 12Sackler Faculty of 64delAGGTGGGGGTCCCC in a Kuwaiti family and Medicine, Tel Aviv University, Tel Aviv, Israel; 13Institute of Child c.146G>C in an Israeli family. VAMP1 is crucial for vesi- Neurology, Schneider Children’s Medical Center of Israel, Petach Tikva, cle fusion at presynaptic neuromuscular junction (NMJ). Israel; and 14Department of Pediatric Neurology, Dubowitz Electrodiagnostic examination showed severely low com- Neuromuscular Centre, Great Ormond Street Hospital for Children pound muscle action potentials and presynaptic impair- National Health Service Foundation Trust, London, United Kingdom ment. We assessed the effect of the nonsense mutation Address correspondence to Dr Houlden, Department of Molecular Neu- on mRNA levels and evaluated the NMJ transmission in roscience, UCL Institute of Neurology, London WC1N 3BG, United lew/lew VAMP1 mice, observing neurophysiological fea- Kingdom, E-mail: [email protected] or Dr Wirth, Institute of Human tures of presynaptic impairment, similar to the patients. Genetics, University of Cologne, Cologne 50931, Germany, E-mail: Taken together, our findings highlight VAMP1 homozy- [email protected]. gous mutations as a cause of presynaptic CMS. ANN NEUROL 2017;81:597–603 *V.S., W.L., and A.D.V. contributed equally to the present work. Additional supporting information can be found in the online version of this article. he congenital myasthenic syndromes (CMSs) are a Received Dec 9, 2016, and in revised form Feb 24, 2017. Accepted for Theterogeneous group of inherited diseases of the neu- publication Feb 24, 2017. romuscular junction (NMJ), with fatigable muscle weak- View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana. 1 ness as the clinical hallmark. Several molecular causes 24905 VC 2017 The Authors. Annals of Neurology Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 597 ANNALS of Neurology records. Neurophysiological studies were performed according feeding difficulties and required percutaneous endoscopic to standard procedures.7,8 gastrostomy. They presented severe impairment of devel- opmental milestones. B.II-1 also showed joint laxity and Genetic Studies kyphoscoliosis. B.II-3 presented knee contractures and Before WES, the Kuwaiti probands (Family 1) underwent exten- sive molecular investigations that included sequencing of AGRN, breathing difficulties. During disease course, both chil- mitochondrial DNA (mtDNA) sequencing, and deletion/duplica- dren showed markedly reduced ability to generate anti- tion analysis and array comparative genome hybridization, which gravity posture and movements. B.II-2 never reached were all negative. Clinical trio-based WES of Family 1 and WGS autonomous walk; his EDX showed severely low CMAPs of the Israeli probands and their parents (Family 2) were per- and increased neuromuscular jitter, indicating NMJ trans- formed as previously described.9,10 Immortalized lymphoblastoid mission abnormalities (see Table 1). In both siblings, pyri- cell lines were used for RNA extraction, reverse transcription dostigmine treatmentimprovedsymptoms. polymerase chain reaction (RT-PCR) analysis, and semiquantita- tive RT-PCR assay. Sanger sequencing was performed to analyze Identification of the VAMP1 Mutation segregation of the variants identified by WES/WGS. Trio-based WES of Family 1 (A.I-1, A.I-2, A.II-1; see Fig 1A) indicated in the index case 3 genes (Supplemen- Vamp1lew/lew Mice tary Table 1) carrying homozygous exonic variants pre- Breeder pairs of Vamp11/lew mice (C3H/HeDiSnJ-Vamp1lew/GrsrJ, dicted to have a possible pathogenic effect on protein stock # 004626) were obtained from the Jackson Laboratory (Bar Harbor, ME) and mated to generate homozygous mutant function, based on the guidelines for variant classifica- 13 (Vamp1lew/lew) mice. Electrophysiological and morphological anal- tion. Full Sanger-based segregation analysis of the can- yses of the NMJ in the Vamp1lew/lew mice were performed as previ- didate variants reduced the gene list to only 1 mutation ously reported.11,12 All experimental protocols were approved by in VAMP1 (NM_014231: c.51_64delAGGTGGGG the University of Texas Southwestern Medical Center institutional GTCCCC; p.Gly18TrpfsTer5*), which was found to be animal care and use committee. homozygous in the affected individuals and heterozygous in their healthy sister and in the unaffected parents Results (see Fig 1C; data shown for the index case and her Clinical and Neurophysiological Characteristics parents). WGS of the 4 members of Family 2 (B.I-2, B.I- FAMILY 1. Both affected individuals A.II-1 and A.II-3 3, B.II-2, B.II-3; see Fig 1B) identified 6 genes carry- (Fig 1A) presented shortly after birth with hypotonia and ing rare (likely) damaging variants (Supplementary muscular weakness. Feeding difficulties requiring gavage Table 2), which were homozygous in the affected indi- feeding, delayed motor development, and ophthalmopa- 12 resis characterized the disease course. A.II-3 also pre- viduals and heterozygous in the parents. Among sented joint contractures. Creatine kinase and plasma lac- these 6 variants, a homozygous missense mutation in > tate were normal in the 2 children. On initial evaluation VAMP1 (NM_014231: c.146G C; p.Arg49Pro; see of Patient A.II-3, muscle biopsy showed myopathic fea- Fig 1D) emerged as the most likely explanation for tures and borderline low complex IV activity (0.011; nor- the disease pathogenesis, as supported by protein func- mal range 5 0.014–0.034), but congenital myopathy tion (the mutation affects a conserved amino acid 14,15 gene panel and mtDNA analysis were negative. Although within the active domain of the protein), expres- 12,16 hypotonia slightly improved in Patient A.II-1, at the age sion and role of this gene in the NMJ, and the of 3 years she still had difficulties standing upright and homozygous mutation identified in the patients was unable to walk without support. Electrodiagnostic from Family 1 presenting the same phenotype (see examination (EDX) in the 2 individuals showed similar Fig 1C–G). findings (Table), with marked reduction in the amplitude RT-PCR assay (performed to analyze possible of the compound muscle action potentials (CMAPs) and nonsense-mediated decay associated with the VAMP1 an increase in the amplitude to >200% of baseline on truncating variant in Family 1) found a mild reduction repetitive nerve stimulation
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