Refinement of the locus for distal hereditary motor neuronopathy VII (dHMN-VII) and exclusion of candidate genes

Abstract

Distal hereditary motor neuronopathy type seven (dHMN-VII) is an autosomal dominant condition characterized by distal muscular atrophy associated with unilateral or bilateral vocal cord paralysis. We previously mapped the dHMN-VII locus to chromosome 2q14 using a genome-wide linkage scan in a single large pedigree. Here we have performed more detailed microsatellite saturation analysis and also evaluated two new affected individuals not described in the original study. We have significantly refined the extent of the disease locus and show that two distinct regions of chromosome 2q14.2, comprising 9.2 Mb and 4.3 Mb separated by an unusual double recombination event, cosegregate with the disease phenotype. The proximal linked region is now defined by markers D2S3038-D2S160, and the distal region by D2S2970-D2S2969. Sequencing of 15 candidate genes within the critical interval has not yet revealed any pathogenic mutations. Inspection of genomic databases indicates that this refinement of the critical interval by 8.4 Mb reduces the number of candidate genes from approximately 400 to approximately 100.

Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization

“…The clinical outcome and nature of the autosomal recessively-acting CHT missense mutations described here overlap with and extend the clinical outcomes recently described due to autosomal recessively-acting SLC5A7 mutations in a CMS-spectrum condition (Bauché et al, 2016), to a more severe impact on brain development associated with early infantile lethality and brain atrophy, as well as abnormal gastrointestinal function. Together these clinical findings and molecular outcomes contrast with those of our previous investigations of dominantly-transmitted dHMN-VII, which we found to be associated with a single base deletion (c.1497delG: p.Lys499Asnfs*13) in SLC5A7 (Pridmore et al, 1992;McEntagart et al, 2001;Dick et al, 2008;Barwick et al, 2012), entailing a near-complete deletion of the transporter's cytoplasmic C-terminus. While this form of hereditary motor neuropathy is also associated with vocal cord paresis, affected individuals display no neurological symptoms early in life and typically present clinically with motor neuron signs only during the second or third decade of life; hypotonia and muscle fatigability is not, to our knowledge, a feature of dHMN-VII.…”

Defective Presynaptic Choline Transport Underlies Hereditary Motor Neuropathy

“…We previously detailed the clinical features of members of a large UK family affected by dominantly transmitted dHMN type VII (dHMN-VII [MIM 158580]), distinguished by the presence of vocal-cord involvement in affected subjects, and we mapped the gene responsible to chromosomal region 2q14. [3][4][5] Here, we report the identification of a mutation within SLC5A7 (MIM 608761) as the under-lying cause of dHMN-VII. SLC5A7 encodes the presynaptic choline transporter (CHT), a critical determinant of synaptic acetylcholine (ACh) synthesis and release at the neuromuscular junction (NMJ).…”

The distal hereditary motor neuropathies

“…If it is due to a mutation in GARS , and there is sensory involvement, it is termed CMT2D. Type VII is defined by vocal-cord paralysis and can be due to mutations in DCTN1, TRPV4 or in an as-yet unidentified gene on chromosome 2q14 6 12 13…”