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: Christian Guelly, Peng-Peng Zhu, Lea Leonardis, Lea Papić, Janez Zidar, Maria Schabhüttl, Heimo Strohmaier, Joachim Weis, Tim M Strom, Jonathan Baets, Jan Willems, Peter De Jonghe, Mary M Reilly, Eleonore Fröhlich, Martina Hatz, Slave Trajanoski, Thomas R Pieber, Andreas R Janecke, Craig Blackstone, Michaela Auer-Grumbach
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 88 Issue 1 Pg. 99-105 (Jan 07 2011) ISSN: 1537-6605 [Electronic] United States
• PMID: 21194679 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• ATL1 protein, human
• GTP Phosphohydrolases
• GTP-Binding Proteins

Topics

• Animals
• Base Sequence
• COS Cells
• Chlorocebus aethiops
• Chromosomes, Human, Pair 14 (genetics)
• Endoplasmic Reticulum (enzymology)
• Exons
• Female
• GTP Phosphohydrolases (genetics)
• GTP-Binding Proteins
• Genes, Dominant
• Hereditary Sensory and Autonomic Neuropathies (genetics)
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• Membrane Proteins
• Molecular Sequence Data
• Mutation
• Mutation, Missense
• Sequence Analysis, DNA
• Spastic Paraplegia, Hereditary (genetics)