Gnathodiaphyseal dysplasia: report of a family with a novel mutation of the ANO5 gene

Abstract

Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant disorder characterized by florid osseous dysplasia (FOD) in the jaws, bone fragility, and diaphyseal cortical thickening and bowing of long bones. We present a family with previously undiagnosed GDD. The disorder was identified by the characteristic gnathic and skeletal manifestations in the father. Clinical and radiological examination of the patient’s son also revealed the characteristic features of GDD. Gene sequencing revealed a novel mutation (c. 1067 G>A, p. Cys356Tyr) in the ANO5 gene, the gene that is causative for GDD. This mutation was predicted to be detrimental by computational analyses and by structural modeling of the protein. The implications for recognition and management of this disease are discussed.

Three novel ANO5 missense mutations in Caucasian and Chinese families and sporadic cases with gnathodiaphyseal dysplasia

“…We also found a novel p.Arg215Gly mutation in sporadic patient 2 who had been clinically and phenotypically described in detail by Riminucci and colleagues 1 . The mutation in Caucasian family 1 (c.1067 G > A; p.Cys356Tyr) has recently been identified in three other families 7 8 9 . These four mutations were not present in publicly available databases which currently include data for more than 6000 genomes (ExAc) and prediction programs SIFT and PolyPhen 2.0 suggested the variants to be potentially damaging.…”

“…GDD is inherited as an autosomal dominant trait or occurs sporadically and was first mapped to an 8.7 cM interval on chromosome 11q14.3–15.1 in a family previously described by Akasaka 5 . Subsequently, three mutations were identified in exon 11 in codon 356 (p.Cys356Arg, p.Cys356Gly and p.Cys356Tyr) 6 7 8 9 . Another missense mutation in exon 15 of ANO5 was found in an Italian family (p.Thr513Ile) 10 and more recently a p.Ser500Phe mutation in a single patient with GDD 11 .…”

Gain of function of TMEM16E/ANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia

“…This syndrome has been associated to mutations in the GDD1 gene [ 36 ], also known as TMEM16E or Ano5 , encoding a 913-amino acid integral membrane protein of unknown physiological function. At present, eight GDD-causing TMEM16E mutations have been identified leading to amino acid exchanges at six positions: p.Arg215Gly [ 17 ], p.Cys356Gly, p.Cys356Arg [ 36 ], p.Cys356Tyr [ 2 , 9 , 17 , 38 ], p.Cys360Tyr [ 17 ], p.Ser500Phe [ 29 ], p.Thr513Ile [ 22 ] and p.Gly518Glu [ 17 ].…”

Diagnostic anoctamin‐5 protein defect in patients with ANO5‐mutated muscular dystrophy

“…No clear genotype–phenotype correlation has been found . Dominant mutations in ANO5 affecting the amino acid C356 cause a completely different phenotype: gnathodiaphyseal dysplasia (GDD; OMIM #166260), a skeletal syndrome .…”