The Novel Gene Encoding a Putative Transmembrane Protein Is Mutated in Gnathodiaphyseal Dysplasia (GDD)

Abstract

Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. By linkage analysis of a large Japanese family with GDD, we previously mapped the GDD locus to chromosome 11p14.3-15.1. In the critical region determined by recombination mapping, we identified a novel gene (GDD1) that encodes a 913-amino-acid protein containing eight putative transmembrane-spanning domains. Two missense mutations (C356R and C356G) of GDD1 were identified in the two families with GDD (the original Japanese family and a new African American family), and both missense mutations occur at the cysteine residue at amino acid 356, which is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis.

ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification

“…ANO2 is predicted to have 8 transmembrane domains with both N and C termini in the cytoplasm, a topology consistent with many ion channels. A mutation in human TMEM16E (ANO5) causes gnathodiaphyseal dysplasia, a disorder characterized by bone calcification defects (17). Bone calcification defects have been noted for mutations in chloride channels (18).…”

Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues

“…GDD is characterized by increased bone fragility, fibro-osseous lesions of the jaw bones, and sclerosis and deformations of tubular bones supporting a role for Ano5 in skeletal development. (28) Here we have analyzed the function of Ano6, the closest paralog of Ano5, during skeletal development. We have identified Ano6 in a subtractive hybridization screen as a potential target gene of Ihh signaling during endochondral ossification (unpublished data).…”

A novel missense mutation in ANO5/TMEM16E is causative for gnathodiaphyseal dyplasia in a large Italian pedigree

“…In human tissues, ANO5 mRNA is detected in the brain, heart, kidney, lung and skeletal muscle, and in mice shows abundant expression in bone tissues including the calvarium, femur and mandible. 4 The recent finding of recessive mutations in ANO5 in patients with proximal LGMD2L (limb-girdle muscular dystrophy-2l) and distal MMD3 (miyoshi muscular dystrophy-3) muscular dystrophies 18,19 complicates the challenge of unraveling the molecular pathophysiology of GDD, which is still unclear.…”