SLC5A7 – Distal hereditary motor neuropathy type 7

Distal hereditary motor neuropathy type 7 (dHMN7) is an autosomal dominant peripheral neuropathy characterized by length-dependent distal muscle weakness and early vocal cord paresis, often presenting initially as singing difficulties due to vocal fold dysfunction. Clinical recognition of dHMN7 has been facilitated by the identification of truncating mutations in the presynaptic high-affinity choline transporter gene, SLC5A7, in multiple unrelated families (PMID:26786006).

Genetic studies of two apparently unrelated Welsh families, including a mother–daughter pair, described a recurrent heterozygous frameshift mutation, c.1497del (p.Lys499fs), which segregates with limb weakness and vocal cord paresis in an autosomal dominant manner, with at least 2 affected relatives in one pedigree (PMID:26786006). Further, permanent truncating variants in the terminal exon have been reported in two additional families with phenotypic variability across upper- and lower-limb predominance, confirming C-terminal CHT truncation as a disease mechanism in dHMN7 (PMID:29582019).

To date, all disease-associated SLC5A7 alleles in dHMN7 are predicted loss-of-function truncations clustering in the last coding exon, without reports of missense or deep-intronic variants. The recurrent c.1497del (p.Lys499fs) truncates regulatory C-terminal trafficking motifs, consistent with impaired choline reuptake.

Functional assays demonstrate that disease-associated truncations act in a dominant-negative manner. Transfected cell lines and patient monocytes exhibit markedly reduced hemicholinium-3–sensitive choline uptake compared to wild type, indicating compromised presynaptic acetylcholine synthesis (PMID:23141292). Cysteine-scanning topology and oligomerization studies reveal that mutant transporters co-assemble with wild-type CHT subunits, exerting dominant-negative inhibition of choline transport activity (PMID:23132865).

No conflicting evidence has been reported to dispute the SLC5A7–dHMN7 association. The concordance of autosomal dominant segregation in at least 3 families, the consistent mutation spectrum, and robust in vitro functional deficits support a strong gene–disease relationship.

Collectively, these data establish that heterozygous truncating SLC5A7 variants underlie dHMN7 via a dominant-negative loss-of-function mechanism. Clinical genetic testing for SLC5A7 truncations, particularly in the terminal exon, is warranted in patients with unexplained distal motor neuropathy and early vocal cord involvement. Accurate molecular diagnosis can inform prognosis and enable targeted management of cholinergic deficits.

Key Take-home: Dominant truncating SLC5A7 mutations cause dHMN7 through impaired choline transport; testing of the terminal exon is essential for diagnosis and therapeutic considerations.

References

• Practical neurology • 2016 • Distal hereditary motor neuropathy with vocal cord paresis: from difficulty in choral singing to a molecular genetic diagnosis. PMID:26786006
• American journal of human genetics • 2012 • Defective presynaptic choline transport underlies hereditary motor neuropathy. PMID:23141292
• The Journal of biological chemistry • 2012 • Transmembrane topology and oligomeric structure of the high-affinity choline transporter. PMID:23132865
• Neurology: Genetics • 2018 • Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies. PMID:29582019

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