A mutation in an alternative untranslated exon of hexokinase 1 associated with Hereditary Motor and Sensory Neuropathy – Russe (HMSNR)

Abstract

Hereditary Motor and Sensory Neuropathy -Russe (HMSNR) is a severe autosomal recessive disorder, identified in the Gypsy population. Our previous studies mapped the gene to 10q22-q23 and refined the gene region to B70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to B26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G4C in a novel alternative untranslated exon (AltT2) and a G4A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls. Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation. Analysis of the Hk1 upstream region in mouse mRNA from testis and neural tissues showed an abundance of AltT2-containing transcripts generated by extensive, developmentally regulated alternative splicing. Expression is very low compared with ubiquitous Hk1 and all transcripts skip exon1, which encodes the protein domain responsible for binding to the outer mitochondrial membrane, and regulation of energy production and apoptosis. Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown and could involve disrupted translational regulation leading to increased anti-apoptotic activity (suggested by the profuse regenerative activity in affected nerves), or impairment of an unknown HK1 function in the peripheral nervous system (PNS).

Plakophilin 2A is the dominant isoform in human heart tissue: consequences for the genetic screening of arrhythmogenic right ventricular cardiomyopathy

“…Although PKP2 transcript and protein from proband A-1 heart tissue were partially degraded owing to poor tissue conservation, we showed that exon 6 splicing was normal in the presence of this variant and did not induce an allele-specific misexpression. As this variant was exclusively identified in patients with ARVC and not in controls, we finally hypothesised that this variant might be in linkage disequilibrium with another non-exonic causative PKP2 mutation that would have been missed by our restricted exonic sequencing protocol 30. We found no additional mutation in the PKP2 regions potentially implicated in transcript expression or stability.…”

Demyelinating CMT–what’s known, what’s new and what’s in store?

“…Caused by mutations in hexokinase 1 or HK1, CMT4G clinical phenotype is characterized by distal lower limb weakness by the first decade with distal upper limb weakness evolving variably from the end of the first decade to the third decade [140,141]. By adolescence proximal lower limbs are usually weak.…”

Fenótipos Raros de Neuropatia Hereditária: Charcot-Marie-Tooth Tipo 4

“…Tal entidade foi inicialmente chamada de neuropatia sensitiva e motora hereditária Russe (HMSNR). Estudos posteriores mostraram que essa variante (CMT4G) estava ligada a uma mutação no cromossomo 10q23.2, especificamente no gene HK1 61 . O gene HK1 codifica um hexoquinase, que cataliza a primeira etapa no metabolismo da glicose.…”