title: 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 approximately 70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to approximately 26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A 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).
authors.affiliation: Laboratory of Molecular Genetics, Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Australia.
authors.forename: Janina
authors.initials: J
authors.lastname: Hantke
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.forename: Rosalind
authors.initials: R
authors.lastname: King
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Dora
authors.initials: D
authors.lastname: Angelicheva
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: Elyshia
authors.initials: E
authors.lastname: McNamara
authors.forename: Marcel
authors.initials: M
authors.lastname: Kwa
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.forename: Radka
authors.initials: R
authors.lastname: Kaneva
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D005091:Exons / Q000235:genetics*; D015417:Hereditary Sensory and Motor Neuropathy / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D006593:Hexokinase / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009424:Nervous System Physiological Phenomena; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology; D020161:Physical Chromosome Mapping; D014176:Protein Biosynthesis / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D006593:Hexokinase