Identification of a novel ANO5 missense mutation in a Chinese family with familial florid osseous dysplasia

• Published in: Journal of human genetics Vol. 64; no. 7; pp. 599 - 607
• Main Authors: Lv, Mingming, You, Guoling, Wang, Jinbing, Fu, Qihua, Gupta, Anand, Li, Jun, Sun, Jian
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-07-2019
• Subjects: Alveoli; Amino acid sequence; Amino acids; Anoctamins - chemistry; Anoctamins - genetics; Bone Density; Cementum; China; Connective tissue diseases; Deoxyribonucleic acid; DNA; Dysplasia; Etiology; Female; Fibrous Dysplasia of Bone - diagnostic imaging; Fibrous Dysplasia of Bone - genetics; Fibrous Dysplasia of Bone - pathology; Genetic counseling; Genomes; Hereditary diseases; Hospitals; Humans; Laboratories; Male; Middle Aged; Missense mutation; Muscular dystrophy; Mutation; Mutation, Missense; Nucleotide sequence; Osteomyelitis - diagnostic imaging; Osteomyelitis - genetics; Osteomyelitis - pathology; Pedigree; Protein Domains; Protein folding; Proteins; Software; Whole Exome Sequencing; China
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-019-0601-9

Familial florid osseous dysplasia (FFOD) is an autosomal dominant disorder of connective tissue, characterized by lobulated cementum-like masses scattered throughout the jaws and the alveolar process. This study aimed to identify the genetic etiology of a three-generation Chinese family affected with FFOD. A novel missense mutation p.C356W in anoctamin 5 (ANO5) gene was successfully identified as the pathogenic mutation by whole-exome sequencing (WES). The p.C356W mutation is located in the first loop between the first and second transmembrane domain of ANO5 protein. Sequence alignment of ANO5 protein among many different species revealed that this position is highly conserved. The p.C356W mutation may damage the predicted protein stability of ANO5 by altering the structure of several extracellular loops of ANO5 and affecting the formation of the disulfide bond, thereby disrupting the correct folding of ANO5 protein. Thus, the amino acid at position 356 appears to play a key role in the protein structural stability and function of ANO5 protein. Our results may also provide new insights into the cause and diagnosis of FFOD and may have implications for genetic counseling and clinical management.