title: Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.
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.
authors.affiliation: Center for Medical Research, Medical University of Graz, Graz 8010, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Guelly
authors.forename: Peng-Peng
authors.initials: PP
authors.lastname: Zhu
authors.forename: Lea
authors.initials: L
authors.lastname: Leonardis
authors.forename: Lea
authors.initials: L
authors.lastname: Papić
authors.forename: Janez
authors.initials: J
authors.lastname: Zidar
authors.forename: Maria
authors.initials: M
authors.lastname: Schabhüttl
authors.forename: Heimo
authors.initials: H
authors.lastname: Strohmaier
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Jan
authors.initials: J
authors.lastname: Willems
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.forename: Martina
authors.initials: M
authors.lastname: Hatz
authors.forename: Slave
authors.initials: S
authors.lastname: Trajanoski
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005091:Exons; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D019204:GTP-Binding Proteins; D005799:Genes, Dominant; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C440006:ATL1 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins