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Guelly, C.* ; Zhu, P.P.* ; Leonardis, L.* ; Papic, L.* ; Zidar, J.* ; Schabhüttl, M.* ; Strohmaier, H.* ; Weis, J.* ; Strom, T.M. ; Baets, J.* ; Willems, J.* ; de Jonghe, P.* ; Reilly, M.M.* ; Fröhlich, E.* ; Hatz, M.* ; Trajanoski, S.* ; Pieber, T.R.* ; Janecke, A.R.* ; Blackstone, C.* ; Auer-Grumbach, M.*

Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.

Am. J. Hum. Genet. 88, 99-105 (2011)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Serine palmitoyltransferase; Spastic paraplegia; Gtpase atlastin; Morphogenesis; Generation; Family
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 88, Issue: 1, Pages: 99-105 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)