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

Abstract

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 4th putative 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.

Novel ANO5 mutation c.1067G>T (p.C356F) identified by whole genome sequencing in a big family with atypical gnathodiaphyseal dysplasia

“…Riminucci et al reported aberrant calcification and thickening of vessel walls and narrowing of the lumens . However, these findings were not reported in the other two articles . In our study, the bone trabeculae were poorly formed and cementum‐like.…”

“…There are three articles reporting the histological features of GDD . All agreed that the pathology shows fibro‐osseous lesions with scattered psammomatoid bodies.…”

“…Variations in clinical manifestations also exist. Bowing of the long bones was not reported in four articles . Jin et al reported a patient who did not experience a bone fracture, although gross thickening of the diaphyseal cortices of long bones was shown by radiograph .…”

“…In 2004, GDD was found to be caused by missense mutations in the ANO5 gene (also known as TMEM16E) . A few recent studies identified six different ANO5 missense mutations in patients with GDD, suggesting an important role of ANO5 missense mutations in the onset of GDD . However, some clinical overlap between GDD and other diseases, such as polyostotic fibrous dysplasia, was found in some patients, indicating that the full spectrum of the GDD phenotype may still remain to be explored .…”

Exploring the genetics underpinning dynamic laryngeal collapse associated with poll flexion in Norwegian‐Swedish Coldblooded Trotter racehorses

“…In humans, ANO3 has been linked to craniocervical dystonia, a disorder affecting muscles of the upper limbs, neck and larynx . Furthermore, ANO5 has been associated with disorders involving both bone and muscle weakness in humans . As a result, both ANO3 and ANO5 appear to warrant further exploration in the horse – particularly with regard to genetic studies of DLC and other URT disorders.…”