Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

被引：64

作者：

Bauche, Stephanie ^{[1
]}

O'Regan, Seana ^{[2
]}

Azuma, Yoshiteru ^{[3
]}

Laffargue, Fanny ^{[4
]}

McMacken, Grace ^{[3
]}

Sternberg, Damien ^{[1
,5
]}

Brochier, Guy ^{[5
,6
]}

Buon, Celine ^{[1
]}

Bouzidi, Nassima ^{[1
]}

Topf, Ana ^{[3
]}

Lacene, Emmanuelle ^{[5
,6
]}

Remerand, Ganaelle ^{[7
]}

Beaufrere, Anne-Marie ^{[8
]}

Pebrel-Richard, Celine ^{[9
]}

Thevenon, Julien ^{[10
,11
,12
]}

El Chehadeh-Djebbar, Salima ^{[13
]}

Faivre, Laurence ^{[10
,11
,12
]}

Duffourd, Yannis ^{[10
]}

Ricci, Federica ^{[14
,15
]}

Mongini, Tiziana ^{[14
,15
]}

Fiorillo, Chiara ^{[16
]}

Astrea, Guja ^{[17
]}

Burloiu, Carmen Magdalena ^{[18
]}

Butoianu, Niculina ^{[18
]}

Sandu, Carmen ^{[18
]}

Servais, Laurent ^{[19
]}

Bonne, Gisele ^{[19
]}

Nelson, Isabelle ^{[19
]}

Desguerre, Isabelle ^{[20
]}

Nougues, Marie-Christine ^{[21
,22
,23
]}

Boeuf, Benoit ^{[24
]}

Romero, Norma ^{[6
]}

Laporte, Jocelyn ^{[25
,26
]}

Boland, Anne ^{[27
]}

Lechner, Doris ^{[27
]}

Deleuze, Jean-Francois ^{[27
]}

Fontaine, Bertrand ^{[1
,5
]}

Strochlic, Laure ^{[1
]}

Lochmuller, Hanns ^{[3
]}

Eymard, Bruno ^{[1
,5
,19
]}

Mayer, Michele ^{[21
,22
,23
]}

Nicole, Sophie ^{[1
]}

机构：

[1] Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France

[2] Paris Descartes Univ, Membrane Transport Grp, Sorbonne Paris Cite, Neurophoton Lab,CNRS,UMR8250, F-75005 Paris, France

[3] Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Inst Med Genet, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[4] Ctr Hosp Univ Clermont Ferrand, Gen Med Serv, Ctr Reference Auvergne Limousin Neuropathies Peri, F-63000 Clermont Ferrand, France

[5] Hop La Pitie Salpetriere, AP HP, F-75013 Paris, France

[6] Univ Paris 06, Sorbonne Univ, Unite Pathol Neuromusculaires, Inst Myol,UMRS 974,INSERM,CNRS,UMR 7215,U974, F-75013 Paris, France

[7] Ctr Hosp Univ Clermont Ferrand, Serv Neonatol, F-63000 Clermont Ferrand, France

[8] Ctr Hosp Univ Clermont Ferrand, Serv Anat & Cytol Pathol, F-63000 Clermont Ferrand, France

[9] Ctr Hosp Univ Clermont Ferrand, Serv Cytogenet Med, F-63000 Clermont Ferrand, France

[10] Ctr Hosp Univ Dijon, Federat Hosp Univ Med Translat & Anomalies Dev TR, F-21079 Dijon, France

[11] Ctr Hosp Univ Dijon, Ctr Genet, F-21079 Dijon, France

[12] Ctr Hosp Univ Dijon, Ctr Reference Anomalies Dev & Syndromes Malformat, F-21079 Dijon, France

[13] Hop Hautepierre, Inst Genet Med Alsace IGMA, Hop Univ Strasbourg, Serv Genet Med, F-67098 Strasbourg, France

[14] Univ Turin, Child Neurol & Psychiat Unit, Ctr Neuromuscular Dis, Regina Margherita Children Hosp, I-10124 Turin, Italy

[15] Univ Turin, Dept Neurosci, I-10124 Turin, Italy

[16] IRCCS Fdn Stella Maris, Mol Med, I-56018 Pisa, Italy

[17] IRCCS Stella Maris Fdn, Dept Dev Neurosci, I-56018 Pisa, Italy

[18] Alexandru Obregia Clin Hosp, Sos Berceni 10-12, Bucharest 041914, Romania

[19] Univ Paris 06, Sorbonne Univ, INSERM, Ctr Res Myol,Myol Inst,CNRS,FRE3617,UMRS974, F-75013 Paris, France

[20] Hop Necker Enfants Malad, Ctr Reference Malad Neuromusculaires Ouest Parisi, F-75743 Paris, France

[21] Hop Enfants Armand Trousseau, Neuropediat, F-75012 Paris, France

[22] Hop Enfants Armand Trousseau, Unite Electrophysiol Clin, Ctr Reference Malad Neuromusculaires EST Parisie, F-75012 Paris, France

[23] Hop Enfants Armand Trousseau, DHU I2B, F-75012 Paris, France

[24] CHU Clermont Ferrand, Hop Estaing, Serv Reanimat Neonatale & Pediat, F-63000 Clermont Ferrand, France

[25] INSERM, U964, Dept Med Translat & Neurogenet, Inst Genet & Biol Mol & Cellulaire,CNRS,UMR 7104, F-67404 Illkirch Graffenstaden, France

[26] Univ Strasbourg, FMTS, F-67000 Strasbourg, France

[27] CNG, F-91057 Evry, France

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2016年 / 99卷 / 03期

基金：

英国医学研究理事会;

关键词：

NEUROMUSCULAR-JUNCTION; RESPIRATORY RHYTHM; KNOCKOUT MOUSE; BUTYRYLCHOLINESTERASE; MUTATIONS; RECEPTORS; ACETYLTRANSFERASE; NEUROTRANSMISSION; DEFICIENCY; EXPRESSION;

D O I：

10.1016/j.ajhg.2016.06.033

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMS5), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.

引用

页码：753 / 761

页数：9

共 34 条

[1] Defective Presynaptic Choline Transport Underlies Hereditary Motor Neuropathy [J].