Three novel ANO5 missense mutations in Caucasian and Chinese families and sporadic cases with gnathodiaphyseal dysplasia.
Gnathodiaphyseal dysplasia (GDD; MIM#166260) is an autosomal dominant syndrome with characteristic cemento-osseous lesions of jawbones, bone fragility, and diaphyseal sclerosis of tubular bones. To date, only five mutations in the proposed calcium-activated chloride channel ANO5/TMEM16E gene have been identified. In this study, we describe two families and two singular patients with three new mutations. One Caucasian family with seven affected members exhibited frequent bone fractures and florid osseous dysplasia (p.Cys356Tyr), while one Chinese family with two affected members suffered from cementoma and purulent osteomyelitis (p.Cys360Tyr). In addition, two different novel mutations (p.Gly518Glu and p.Arg215Gly) were identified in sporadic patients without family history. In vitro studies overexpressing GDD mutations (p.Cys356Tyr and p.Cys360Tyr) showed significantly reduced ANO5 protein. It appears that all GDD mutations known so far locate in an extracellular domain following the first transmembrane domain or in the 4thputative transmembrane domain. Both wild-type and mutant ANO5 protein localize to the endoplasmic reticulum. After Ano5 gene knock-down with shRNA in MC3T3-E1 osteoblast precursors we saw elevated expression of osteoblast-related genes such as Col1a1, osteocalcin, osterix and Runx2 as well as increased mineral nodule formation in differentiating cells. Our data suggest that ANO5 plays a role in osteoblast differentiation.
Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.
Lingling
L
Jin
Department of Maxillofacial Surgery, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.
Yi
Y
Liu
Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, University of Connecticut Health, Farmington, CT, 06030, USA.
Fanyue
F
Sun
National Institute of Dental and Craniofacial Research (NIDCR), Bethesda, MD, 20892, USA.
Michael T
MT
Collins
Department of Head and Neck Surgery, UCLA, Los Angeles, CA, 90095, USA.
Keith
K
Blackwell
Division of Plastic Craniofacial and Pediatric Surgery, Brown University Warren Alpert Medical School, Providence, RI, 02903, USA.
Albert S
AS
Woo
Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, University of Connecticut Health, Farmington, CT, 06030, USA.
Ernst J
EJ
Reichenberger
Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.
Ying
Y
Hu
D000293:Adolescent; D000328:Adult; D000368:Aged; D000075368:Anoctamins / Q000235:genetics*; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*; D044465:White People
C547813:ANO5 protein, human; D000075368:Anoctamins