Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation.
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.
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Ranad
R
Shaheen
Anas M
AM
Alazami
Muneera J
MJ
Alshammari
Eissa
E
Faqeih
Nadia
N
Alhashmi
Noon
N
Mousa
Aisha
A
Alsinani
Shinu
S
Ansari
Fatema
F
Alzahrani
Mohammed
M
Al-Owain
Zayed S
ZS
Alzayed
Fowzan S
FS
Alkuraya
D001083:Arabia; D001483:Base Sequence; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D003241:Consanguinity; D005091:Exons; D005260:Female; D023061:Gene Order; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics*
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D007473:Ion Channels; C578840:TMEM38B protein, human