Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations.
Bottom Line: Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Na(v)1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Na(v)1.7-DeltaR1370-L1374).Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type.In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Na(v)1.7.
Affiliation: Department of Medical Genetics, University of Cambridge, UK.Show MeSH
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Mentions: The patients belong to a consanguineous family, one father with 2 first degree cousin wives (Figure 1a). We studied three sisters of the same nuclear family. Two of the girls were the offspring of one wife and another patient was the daughter of the second wife to the same father. Their ages were 15, 5 and 3 years respectively. The pregnancy and delivery were normal. All presented with a history of indifference to pain in early childhood, e.g. pin pricks or falls, with recurrent trauma including skin burns, fracture of bones and amputation of toes which caused them little distress. All patients had old skin scars due to burns, frequent cuts and bruises. Deformities of the limbs due to osteomyelitis of the upper and lower limbs and old bone fractures were evident, including a fracture of the shoulder which was identified by local swelling in one patient and a tibial bone fracture which was noticed due to limping in another. Trauma of the oral region was frequent in all patients. The tips of the tongues were amputated due to recurrent biting. The patients extracted their teeth and suffered from recurrent bouts of mandibular osteomyelitis. On examination the children were able to feel fine touch and pin prick but were indifferent to painful stimuli caused by squeezing the Achilles tendon and finger tips. In addition, they showed a normal histamine flare response, sweated normally and had normal intelligence. Nerve conduction studies performed in 2 of the patients revealed normal motor conduction with borderline reduction in the medial plantar sensory action potential (SAP). Their corneal responses were reduced. The patients presented the clinical picture of CIP and had no features of other hereditary sensory neuropathies. Specifically, the phenotype differed from patients with Congenital Insensitivity to Pain with Anhydrosis (CIPA; MIM# 256800) in that all had normal cognitive development, lack of unexplained bouts of fever in infancy and early childhood, normal lacrimal product and sweat, and normal sympathetic skin responses. The study was approved by the Soroka Helsinki committee. See Supp. Methods for more information.
Affiliation: Department of Medical Genetics, University of Cambridge, UK.