title: Two novel mutations of SCN9A (Nav1.7) are associated with partial congenital insensitivity to pain.
abstract: Insensitivity to pain is a rare disorder that is commonly associated with Hereditary Sensory and Autonomic Neuropathies (HSAN I-V) resulting often in autonomic dysfunction and premature death. Very few individuals have been reported with pain insensitivity lacking such autonomic neuropathies. We performed genetic, neurologic, psychological, and psychophysical evaluations in such an individual (OMIM 243000) and her first degree relatives. Sequence analysis of genomic DNA revealed two novel SCN9A mutations in this index case (IC). One was a non-conservative missense mutation (C1719R) in exon 26 present only in the IC and one parent. Further sequence analysis of the child's DNA revealed a 1-bp splice donor deletion in intron 17 which was also present in the other parent and one sibling. Detailed psychophysical testing was used to phenotypically characterize the IC, her family members, and 10 matched normal controls. Similar to family members and controls the IC showed normal somatosensory functioning for non-nociceptive mechanoreception and warmth. However, she demonstrated diminished ability to detect cool temperatures combined with profound deficits in heat and mechanical nociception. Congenital insensitivity to pain in our IC was associated with two novel SCN9A mutations which most likely resulted in a Nav1.7 channelopathy. However, in contrast to individuals with other SCN9A mutations, the observed pain insensitivity was relative and not absolute, which may be consistent with hypomorphic effects of one or both mutations. The ability to sense at least some danger signals may be advantageous and ameliorate the otherwise increased morbidity and mortality of some individuals with congenital insensitivity to pain.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL 32610, United States. staudr@ufl.edu
authors.forename: Roland
authors.initials: R
authors.lastname: Staud
authors.forename: Donald D
authors.initials: DD
authors.lastname: Price
authors.forename: David
authors.initials: D
authors.lastname: Janicke
authors.forename: Edgard
authors.initials: E
authors.lastname: Andrade
authors.forename: Angela G
authors.initials: AG
authors.lastname: Hadjipanayis
authors.forename: Will T
authors.initials: WT
authors.lastname: Eaton
authors.forename: Lee
authors.initials: L
authors.lastname: Kaplan
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
mesh_terms: D000328:Adult; D002648:Child; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D000699:Pain Insensitivity, Congenital / Q000235:genetics*; D010147:Pain Measurement; D058748:Pain Perception / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation; D016133:Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics*; D011795:Surveys and Questionnaires
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels