Homozygous Mutations in VAMP1 Cause a Presynaptic Congenital Myasthenic Syndrome

被引：56

作者：

Salpietro, Vincenzo ^{[1
]}

Lin, Weichun ^{[2
]}

Delle Vedove, Andrea ^{[3
,4
]}

Storbeck, Markus ^{[3
,4
]}

Liu, Yun ^{[2
]}

Efthymiou, Stephanie ^{[1
]}

Manole, Andreea ^{[1
]}

Wiethoff, Sarah ^{[1
]}

Ye, Qiaohong ^{[2
]}

Saggar, Anand ^{[5
]}

McElreavey, Kenneth ^{[6
]}

Krishnakumar, Shyam S. ^{[7
,8
]}

Pitt, Matthew

Bello, Oscar D. ^{[7
,8
]}

Rothman, James E. ^{[7
,8
]}

Basel-Vanagaite, Lina ^{[10
,11
,12
]}

Hubshman, Monika Weisz ^{[10
,11
,12
]}

Aharoni, Sharon ^{[12
,13
]}

Manzur, Adnan Y. ^{[14
]}

Wirth, Brunhilde ^{[3
]}

Houlden, Henry ^{[1
]}

机构：

[1] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA

[3] Inst Human Genet, Ctr Mol Med Cologne, Cologne, Germany

[4] Univ Cologne, Inst Genet, Cologne, Germany

[5] St George Hosp, Natl Hlth Serv Fdn Trust, London, England

[6] Inst Pasteur, Human Dev Genet, Paris, France

[7] Yale Sch Med, Dept Cell Biol, New Haven, CT USA

[8] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London, England

[9] Great Ormond St Hosp Sick Children, Natl Hlth Serv Fdn Trust, Dept Clin Neurophysiol, London, England

[10] Schneider Childrens Med Ctr Israel, Pediat Genet Unit, Petah Tiqwa, Israel

[11] Raphael Recanati Genet Inst, Rabin Med Ctr, Petah Tiqwa, Israel

[12] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[13] Schneider Childrens Med Ctr Israel, Inst Child Neurol, Petah Tiqwa, Israel

[14] Great Ormond St Hosp Sick Children, Natl Hlth Serv Fdn Trust, Dubowitz Neuromuscular Ctr, Dept Pediat Neurol, London, England

来源：

ANNALS OF NEUROLOGY | 2017年 / 81卷 / 04期

基金：

美国国家卫生研究院; 英国惠康基金; 英国医学研究理事会;

关键词：

NEUROTRANSMITTER RELEASE; NEUROMUSCULAR-JUNCTION; SNARE COMPLEX; EXOCYTOSIS; DIAGNOSIS; VARIANTS; FUSION; MUTANT;

D O I：

10.1002/ana.24905

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1(lew/lew) mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS.

引用

页码：597 / 603

页数：7

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