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J Neurol Neurosurg Psychiatry 84:386-391 doi:10.1136/jnnp-2012-303719
  • Neurogenetics
  • Research paper

Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia

Open Access
  1. Peter J Dyck1
  1. 1Department of Neurology, Division of Peripheral Nerve Diseases, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  4. 4Department of Neurology, Auckland District Health Board, New Zealand
  5. 5Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Christopher J Klein, Department of Neurology, Division of Peripheral Nerve Diseases, Mayo Clinic, Rochester, MN 55905, USA; klein.christopher{at}mayo.edu
  • Received 19 July 2012
  • Revised 5 October 2012
  • Accepted 9 October 2012
  • Published Online First 5 November 2012

Abstract

Objective Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia.

Methods We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes.

Results In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations.

Conclusions Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

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