TY - JOUR
T1 - KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2
AU - Rivire, Jean Baptiste
AU - Ramalingam, Siriram
AU - Lavastre, Valérie
AU - Shekarabi, Masoud
AU - Holbert, Sébastien
AU - Lafontaine, Julie
AU - Srour, Myriam
AU - Merner, Nancy
AU - Rochefort, Daniel
AU - Hince, Pascale
AU - Gaudet, Rébecca
AU - Mes-Masson, Anne Marie
AU - Baets, Jonathan
AU - Houlden, Henry
AU - Brais, Bernard
AU - Nicholson, Garth A.
AU - Van Esch, Hilde
AU - Nafissi, Shahriar
AU - De Jonghe, Peter
AU - Reilly, Mary M.
AU - Timmerman, Vincent
AU - Dion, Patrick A.
AU - Rouleau, Guy A.
PY - 2011/8/12
Y1 - 2011/8/12
N2 - Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system.
AB - Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system.
UR - http://www.scopus.com/inward/record.url?scp=80051663564&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.06.013
DO - 10.1016/j.ajhg.2011.06.013
M3 - Article
C2 - 21820098
AN - SCOPUS:80051663564
SN - 0002-9297
VL - 89
SP - 219
EP - 301
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -