Title: KIF1A, an Axonal Transporter of Synaptic Vesicles, Is Mutated in Hereditary Sensory and Autonomic Neuropathy Type 2
Authors: Rivière, Jean-Baptiste ×
Ramalingam, Siriram
Lavastre, Valérie
Shekarabi, Masoud
Holbert, Sébastien
Lafontaine, Julie
Srour, Myriam
Merner, Nancy
Rochefort, Daniel
Hince, Pascale
Gaudet, Rébecca
Mes-Masson, Anne-Marie
Baets, Jonathan
Houlden, Henry
Brais, Bernard
Nicholson, Garth A
Van Esch, Hilde
Nafissi, Shahriar
De Jonghe, Peter
Reilly, Mary M
Timmerman, Vincent
Dion, Patrick A
Rouleau, Guy A #
Issue Date: Aug-2011
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:89 issue:2 pages:219-230
Abstract: 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.
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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