期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 88, 期 1, 页码 99-105出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2010.12.003
关键词
-
资金
- Austrian Science Fund (FWF) [P19455-B05]
- Oesterreichische Nationalbank (ONB) [13010]
- National Institute of Neurological Disorders and Stroke, US National Institutes of Health
- University of Antwerp
- Fund for Scientific Research (FWO-Flanders)
- Medical Foundation Queen Elisabeth (GSKE)
- Association Beige contre les Maladies Neuromusculaires (ABMM)
- Interuniversity Attraction Poles Program of the Belgian Federal Science Policy Office (BELSPO) [P6/43]
- Deutsche Forschungsgemeinschaft [WE 1406 13/1]
- MRC [G0601943] Funding Source: UKRI
- Austrian Science Fund (FWF) [P19455] Funding Source: Austrian Science Fund (FWF)
- Medical Research Council [G0601943] Funding Source: researchfish
Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据