title: A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type.
abstract: The Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. Several genes have been implicated to result in EDS phenotypes. The progeroid type of EDS is characterized by wrinkled, loose skin on the face, curly fine hair, scanty eyebrows and eyelashes, in addition to the classical features of EDS. Here we describe two similarly affected individuals in two sibships of a large consanguineous family from Qatar. DNA samples from affected and unaffected members of the family were analyzed for homozygosity of polymorphic markers associated with genes that have been implicated in EDS. Among 28 markers analyzed, homozygosity was only observed for D5S469 and D5S2111, which were markers for galactosyltransferase-I (B4GALT7) located on chromosome 5q35.2, where the previously reported progeroid-like variant of EDS has been mapped. Exons harboring the coding regions and exon-intron junctions of B4GALT7 were amplified by PCR and examined for mutations. A homozygous misssense C to T substitution at nucleotide 808 in the coding region was discovered in both affected individuals. The carrier parents were heterozygous for this mutation, which was not found among 76 DNA samples from control individuals of the same ethnicity. Segregation of this novel mutation in the family further confirmed the allelic variant and its recessive mode of inheritance in this type of EDS. The C to T substitution results in an arginine to cysteine change at amino acid residue 270 that is located in the catalytically active extracellular C-terminal domain. This change could result in abnormal protein folding and/or aberrant interactions of mutated galactosyltransferase-I with other extracellular matrix proteins leading to the development of a progeroid-like phenotype in affected individuals.
authors.affiliation: Program in Genetics and Genomic Biology, Department of Genetics, The Hospital for Sick Children, 9th Floor Elm Wing, Rm. 9115, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. muhammad@genet.sickkids.on.ca
authors.forename: Muhammad
authors.initials: M
authors.lastname: Faiyaz-Ul-Haque
authors.forename: Syed Hassan Ejaz
authors.initials: SH
authors.lastname: Zaidi
authors.forename: Mariam
authors.initials: M
authors.lastname: Al-Ali
authors.forename: Mariam S
authors.initials: MS
authors.lastname: Al-Mureikhi
authors.forename: Shelley
authors.initials: S
authors.lastname: Kennedy
authors.forename: Ghalia
authors.initials: G
authors.lastname: Al-Thani
authors.forename: Lap-Chee
authors.initials: LC
authors.lastname: Tsui
authors.forename: Ahmad Said
authors.initials: AS
authors.lastname: Teebi
mesh_terms: D000328:Adult; D001842:Bone and Bones / Q000002:abnormalities; D004247:DNA / Q000032:analysis; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology; D005145:Face / Q000002:abnormalities; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: D005819:Genetic Markers; D004247:DNA; D005700:Galactosyltransferases; C063053:xylosylprotein 4-beta-galactosyltransferase