BACKGROUND: Osteogenesis imperfecta (OI) is an hereditary bone disease in which increased bone fragility leads to frequent fractures and other complications, usually in an autosomal dominant fashion. An expanding list of genes that encode proteins related to collagen metabolism are now recognised as important causes of autosomal recessive (AR) OI. Our aim was to study the contribution of known genes to AR OI in order to identify novel loci in mutation-negative cases. METHODS: We enrolled multiplex consanguineous families and simplex cases (also consanguineous) in which mutations in COL1A1 and COL1A2 had been excluded. We used autozygome guided mutation analysis of AR OI (AR OI) genes followed by exome sequencing when such analysis failed to identify the causative mutation. RESULTS: Two simplex and 11 multiplex families were enrolled, encompassing 27 cases. In three multiplex families, autozygosity and linkage analysis revealed a novel recessive OI locus on chromosome 9q31.1-31.3, and a novel truncating deletion of exon 4 of TMEM38B was identified within that interval. In addition, gonadal or gonadal/somatic mosaic mutations in COL1A1 or COL1A2 and homozygous mutations in recently described AR OI genes were identified in all remaining families. CONCLUSIONS: TMEM38B is a novel candidate gene for AR OI. Future studies are needed to explore fully the contribution of this gene to AR OI in other populations.
BACKGROUND:Osteogenesis imperfecta (OI) is an hereditary bone disease in which increased bone fragility leads to frequent fractures and other complications, usually in an autosomal dominant fashion. An expanding list of genes that encode proteins related to collagen metabolism are now recognised as important causes of autosomal recessive (AR) OI. Our aim was to study the contribution of known genes to AR OI in order to identify novel loci in mutation-negative cases. METHODS: We enrolled multiplex consanguineous families and simplex cases (also consanguineous) in which mutations in COL1A1 and COL1A2 had been excluded. We used autozygome guided mutation analysis of AR OI (AR OI) genes followed by exome sequencing when such analysis failed to identify the causative mutation. RESULTS: Two simplex and 11 multiplex families were enrolled, encompassing 27 cases. In three multiplex families, autozygosity and linkage analysis revealed a novel recessive OI locus on chromosome 9q31.1-31.3, and a novel truncating deletion of exon 4 of TMEM38B was identified within that interval. In addition, gonadal or gonadal/somatic mosaic mutations in COL1A1 or COL1A2 and homozygous mutations in recently described AR OI genes were identified in all remaining families. CONCLUSIONS:TMEM38B is a novel candidate gene for AR OI. Future studies are needed to explore fully the contribution of this gene to AR OI in other populations.
Authors: Renata Moldenhauer Minillo; Nara Sobreira; Maria de Fatima de Faria Soares; Julie Jurgens; Hua Ling; Kurt N Hetrick; Kimberly F Doheny; David Valle; Decio Brunoni; Ana B Alvarez Perez Journal: Mol Syndromol Date: 2014-11-25
Authors: Xinyu Zhou; Peihui Lin; Daiju Yamazaki; Ki Ho Park; Shinji Komazaki; S R Wayne Chen; Hiroshi Takeshima; Jianjie Ma Journal: Circ Res Date: 2014-02-14 Impact factor: 17.367
Authors: Shawna M Pyott; Thao T Tran; Dru F Leistritz; Melanie G Pepin; Nancy J Mendelsohn; Renee T Temme; Bridget A Fernandez; Solaf M Elsayed; Ezzat Elsobky; Ishwar Verma; Sreelata Nair; Emily H Turner; Joshua D Smith; Gail P Jarvik; Peter H Byers Journal: Am J Hum Genet Date: 2013-03-14 Impact factor: 11.025
Authors: Katharina Keupp; Filippo Beleggia; Hülya Kayserili; Aileen M Barnes; Magdalena Steiner; Oliver Semler; Björn Fischer; Gökhan Yigit; Claudia Y Janda; Jutta Becker; Stefan Breer; Umut Altunoglu; Johannes Grünhagen; Peter Krawitz; Jochen Hecht; Thorsten Schinke; Elena Makareeva; Ekkehart Lausch; Tufan Cankaya; José A Caparrós-Martín; Pablo Lapunzina; Samia Temtamy; Mona Aglan; Bernhard Zabel; Peer Eysel; Friederike Koerber; Sergey Leikin; K Christopher Garcia; Christian Netzer; Eckhard Schönau; Victor L Ruiz-Perez; Stefan Mundlos; Michael Amling; Uwe Kornak; Joan Marini; Bernd Wollnik Journal: Am J Hum Genet Date: 2013-03-14 Impact factor: 11.025