Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations
Female; Humans; Male; Mutation; DNA Mutational Analysis; Pedigree; Chromosomes; Human; Genetics; Population; Chromosome Mapping; Haplotypes; Pair 2/genetics; Codon; Congenital/genetics; Founder Effect; Frameshift Mutation; Nonsense; Pain Insensitivity; Sequence Deletion; Sodium Channels/genetics
Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.
2007
Goldberg YP; MacFarlane J; MacDonald ML; Thompson J; Dube MP; Mattice M; Fraser R; Young C; Hossain S; Pape T; Payne B; Radomski C; Donaldson G; Ives E; Cox J; Younghusband HB; Green R; Duff A; Boltshauser E; Grinspan GA; Dimon JH; Sibley BG; Andria G; Toscano E; Kerdraon J; Bowsher D; Pimstone SN; Samuels ME; Sherrington R; Hayden MR
Clinical Genetics
2007
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1111/j.1399-0004.2007.00790.x" target="_blank" rel="noreferrer">10.1111/j.1399-0004.2007.00790.x</a>
Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis
Child; Female; Humans; Male; Mutation; P.H.S.; Research Support; U.S. Gov't; Syndrome; infant; Models; Pedigree; Membrane Proteins/genetics; Base Sequence; Amino Acid Sequence; Exons; Genes; Recessive; Missense; Molecular; Chromosome Mapping; Fibroma/genetics; Genetic Markers; Focal/genetics; Glomerulosclerosis; Protein Conformation; Protein Structure; Secondary
Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG-2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a von Willebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.
2003
Dowling O; Difeo A; Ramirez MC; Tukel T; Narla G; Bonafe L; Kayserili H; Yuksel-Apak M; Paller AS; Norton K; Teebi AS; Grum-Tokars V; Martin GS; Davis GE; Glucksman MJ; Martignetti JA
American Journal Of Human Genetics
2003
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1086/378781" target="_blank" rel="noreferrer">10.1086/378781</a>
A Genomewide Linkage-Disequilibrium Scan Localizes the Saguenay -Lac-Saint-Jean Cytochrome Oxidase Deficiency to 2p16
Female; Humans; Male; Mutation; Family Health; Gene Frequency; Molecular Sequence Data; DNA Mutational Analysis; DNA/chemistry/genetics; Pedigree; Chromosomes; Human; Base Sequence; Disease Specific; Chromosome Mapping; Cytochrome-c Oxidase Deficiency; Electron Transport Complex IV/genetics; Genes/genetics; Genome; Haplotypes; Leigh Disease/enzymology/genetics; Linkage Disequilibrium; Microsatellite Repeats; Pair 2/genetics; Polymorphism; Single Nucleotide
2001
Lee N; Daly MJ; Delmonte T; Lander ES; Xu F; Hudson TJ; Mitchell GA; Morin CC; Robinson BH; Rioux JD
American Journal Of Human Genetics
2001
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1086/318197" target="_blank" rel="noreferrer">10.1086/318197</a>
Neurodegenerative disease: the neuronal ceroid lipofuscinoses (Batten disease)
Child; Phenotype; infant; Models; Membrane Proteins/genetics; Human; Genetic; Animal; Genotype; Chromosome Mapping; Proteins/genetics; Neuronal Ceroid-Lipofuscinosis/diagnosis/genetics/therapy; Phosphoprotein Phosphatase/genetics
In the past decade there have been significant advances in our understanding of the molecular genetic basis of the neuronal ceroid lipofuscinoses, a clinically and genetically heterogeneous group of childhood neurodegenerative storage disorders. Recent research progress is reviewed here, to summarize new disease gene identification, diagnostics, treatment, protein functional studies and investigations into the underlying molecular pathogenesis of these devastating disorders.
2001
Mitchison HM; Mole SE
Current Opinion In Neurology
2001
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article