Defective Presynaptic Choline Transport Underlies Hereditary Motor Neuropathy

Katy E.S Barwick,Jane Wright,Saeed Al-Turki,Meriel M Mcentagart,Ajith Nair,Barry Chioza,Ali Al-Memar,Hamid Modarres,Mary M Reilly,Katherine J Dick,Alicia M Ruggiero,Randy D Blakely,Matt E Hurles,Andrew H Crosby

doi:10.1016/j.ajhg.2012.09.019

Abstract

The neuromuscular junction (NMJ) is a specialized synapse with a complex molecular architecture that provides for reliable transmission between the nerve terminal and muscle fiber. Using linkage analysis and whole-exome sequencing of DNA samples from subjects with distal hereditary motor neuropathy type VII, we identified a mutation in SLC5A7, which encodes the presynaptic choline transporter (CHT), a critical determinant of synaptic acetylcholine synthesis and release at the NMJ. This dominantly segregating SLC5A7 mutation truncates the encoded product just beyond the final transmembrane domain, eliminating cytosolic-C-terminus sequences known to regulate surface transporter trafficking. Choline-transport assays in both transfected cells and monocytes from affected individuals revealed significant reductions in hemicholinium-3-sensitive choline uptake, a finding consistent with a dominant-negative mode of action. The discovery of CHT dysfunction underlying motor neuropathy identifies a biological basis for this group of conditions and widens the spectrum of disorders that derive from impaired NMJ transmission. Our findings compel consideration of mutations in SLC5A7 or its functional partners in relation to unexplained motor neuronopathies.

Highlights

The neuromuscular junction (NMJ) is a specialized synapse with a complex molecular architecture that provides for reliable transmission between the nerve terminal and muscle fiber
We previously detailed the clinical features of members of a large UK family affected by dominantly transmitted distal hereditary motor neuronopathies (dHMNs) type VII, distinguished by the presence of vocal-cord involvement in affected subjects, and we mapped the gene responsible to chromosomal region 2q14.3–5 Here, we report the identification of a mutation within SLC5A7 (MIM 608761) as the underlying cause of dHMN-VII
Mutations affecting genes coding for NMJ proteins are well known to cause a contrasting phenotype of congenital myasthenic syndrome, which is characterized by fatiguing muscle weakness and cranialnerve and respiratory-muscle involvement.[6]

Summary

Introduction

The neuromuscular junction (NMJ) is a specialized synapse with a complex molecular architecture that provides for reliable transmission between the nerve terminal and muscle fiber. In order to identify the disease-associated gene, we performed whole-exome sequencing of a single affected individual (VI:5) in this family (Figure 1).

Results

Conclusion