Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Caus

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Am J Hum Genet. 2010 Dec 29

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a

Cause of Hereditary Sensory Neuropathy Type I.

Guelly C, Zhu PP, Leonardis L, Papi & #263; L, Zidar J, Schabhüttl M, Strohmaier

H, Weis J, Strom TM, Baets J, Willems J, De Jonghe P, Reilly MM, Fröhlich E,

Hatz M, Trajanoski S, Pieber TR, Janecke AR, Blackstone C, Auer-Grumbach M.

Center for Medical Research, Medical University of Graz, Graz 8010, Austria.

Abstract

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.