Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

Bauche Stephanie; Vellieux Geoffroy; Sternberg Damien; Fontenille Marie-Josephine; De Bruyckere Elodie; Davoine Claire-Sophie; Brochier Guy; Messeant Julien; Wolf Lucie; Fardeau Michel; Lacene Emmanuelle; Romero Norma; Koenig Jeanine; Fournier Emmanuel; Hantai Daniel; Streichenberger Nathalie; Manel Veronique; Lacour Arnaud; Nadaj-Pakleza Aleksandra; Sukno Sylvie; Bouhour Francoise; Laforet Pascal; Fontaine Bertrand; Strochlic Laure; Eymard Bruno; Chevessier Frederic; Stojkovic Tanya; Nicole Sophie

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Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

机译：GFPT1相关的先天性症状综合征中的突变与突触形态缺陷与突触症的管状骨膜病变有关

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Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients' muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a "tubular aggregates myopathy with synaptopathy".

机译：GFPT1（谷氨酰胺 - 果糖-6-磷酸转氨酶1）中的突变，编码参与普遍蛋白质的糖基化的酶的基因，导致肢体与管状聚集体（TA）引起肢体染发剂综合征（LG-CMS），其主要是受到影响的患者肌肉活组织检查中近端骨骼肌和高度有组织和改造的肌肉小管的存在。我们在这里报告了11名患有GFPT1突变引起的LG-CMS的11名法国人的第一个长期临床随访，其中九个是新的。我们的回顾性临床评估强调了一种趋于近似地发生的肌病弱点的演变，以常见的是常用的CMS治疗的效果。来自三个无关个体的神经肌肉活组织检查分析表明，由于影响三个主要NMJ组分的突触后连接折叠和证据，显着损害了神经肌肉连接（NMJ）的维持。此外，人肌肉活组织检查的分子分析确认了蛋白质的糖基化缺陷，其具有降低的o-糖基化，并显示出超近区域中的跨膜蛋白的唾液酸化。总共，这些结果为理解这种罕见神经肌病病症的病因铺平了这种罕见的神经肌病病因，这些病因可能被认为是“与突触角病的管状聚集体肌病”。

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《Journal of neurology》 |2017年第8期|共13页
作者
Bauche Stephanie; Vellieux Geoffroy; Sternberg Damien; Fontenille Marie-Josephine; De Bruyckere Elodie; Davoine Claire-Sophie; Brochier Guy; Messeant Julien; Wolf Lucie; Fardeau Michel; Lacene Emmanuelle; Romero Norma; Koenig Jeanine; Fournier Emmanuel; Hantai Daniel; Streichenberger Nathalie; Manel Veronique; Lacour Arnaud; Nadaj-Pakleza Aleksandra; Sukno Sylvie; Bouhour Francoise; Laforet Pascal; Fontaine Bertrand; Strochlic Laure; Eymard Bruno; Chevessier Frederic; Stojkovic Tanya; Nicole Sophie;
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作者单位

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

Hop La Pitie Salpetriere AP HP F-75013 Paris France;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

Univ Hosp Erlangen Inst Neuropathol Schwabachanlage 6 Erlangen Germany;

Hop La Pitie Salpetriere AP HP F-75013 Paris France;

Hop La Pitie Salpetriere AP HP F-75013 Paris France;

Hop La Pitie Salpetriere AP HP F-75013 Paris France;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

Univ Claude Bernard Lyon1 Hosp Civils Lyon Ctr Neuropathol Est Inst NeuroMyogene CNRS UMR 5310;

Hop Femme Mere Enfant Serv Epileptol Clin Troubles Sommeil &

Neurol Foc Lyon France;

CHRU Lille Hop Roger Salengro Clin Neurol Rue Emile Laine Lille France;

CHU Angers Ctr Reference Malad Neuromusculaires Nantes Anger Serv Neurol F-49933 Angers France;

Ctr Hosp Bethune Beuvry Serv Consultat Externes Pediat F-62408 Bethune France;

Hosp Civils Lyon Serv ENMG Pathol Neuromusculaires Hop Neurol Pierre Wertheimer F-69677 Lyon;

Hop La Pitie Salpetriere AP HP F-75013 Paris France;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

Univ Hosp Erlangen Inst Neuropathol Schwabachanlage 6 Erlangen Germany;

Hop La Pitie Salpetriere AP HP F-75013 Paris France;

UPMC Univ Paris 06 Sorbonne Univ Hop la Pitie Salpetriere ICM Inserm U 1127 CNRS UMR 7225 UMR S;

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正文语种 eng
中图分类神经病学;
关键词
Limb-girdle myasthenia; GFPT1; Tubular aggregates; Neuromuscular junction; Myopathy;

机译：肢体肌炎;gfpt1;管状聚集体;神经肌肉交叉点;肌病;

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专利

1. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy [J] . Bauche Stephanie, Vellieux Geoffroy, Sternberg Damien, Journal of neurology . 2017,第8期

机译：GFPT1相关的先天性症状综合征中的突变与突触形态缺陷与突触症的管状骨膜病变有关
2. The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome [J] . Judith Cossins1 Wei Wei Liu1 Katsiaryna Belaya1 Susan Maxwell1 Michael Oldridge3 Tracy Lester3 Stephanie Robb2 and David Beeson1* Human Molecular Genetics . 2012,第17期

机译：DOK7先天性肌无力综合症中神经肌肉接头突触病基础突变的频谱
3. Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations [J] . GuergueltchevaV., MüllerJ.S., DuslM., Journal of neurology . 2012,第5期

机译：先天性肌无力综合征，由GFPT1突变引起的肾小管聚集
4. Synaptic basal lamina–associated congenital myasthenic syndromes [C] . Ricardo A. Maselli, Juan Arredondo, Michael J. Ferns, International Conference on Myasthenia Gravis and Related Disorders . 2012

机译：Synaptic Basal Lamina相关的先天性染色综合征
5. Mouse Models of Periodic Paralysis in Andersen Tawil Syndrome and Functional Studies of Novel Nav1.4 Mutations in Myotonia & Myopathy [D] . ?Elia, Nathaniel Curtis 2020

机译：安德森三伐综合征治疗术后瘫痪的小鼠模型和新型NAV1.4突变术中的肌疗法突变功能研究
6. Mutations in DPAGT1 Cause a Limb-Girdle Congenital Myasthenic Syndrome with Tubular Aggregates [O] . Katsiaryna Belaya, Sarah Finlayson, Clarke R. Slater, 2012

机译：DPAGT1中的突变导致管状骨聚集的四肢先天性肌无力综合征。
7. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy [O] . Bauché, Stéphanie, Vellieux, Geoffroy, Sternberg, Damien, 2017

机译：GFPT1相关的先天性肌无力综合征的突变与突触的形态学缺陷相关，并且是伴有突触病的肾小管聚集性肌病的基础

Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

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