Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families

Abstract

Tooth development is controlled by the same processes that regulate formation of other ectodermal structures. Mutations in the genes underlying these processes may cause ectodermal dysplasia, including severe absence of primary or permanent teeth. Four consanguineous Palestinian families presented with oligodontia and hair and skin features of ectodermal dysplasia. Appearance of ectodermal dysplasia was consistent with autosomal recessive inheritance. Exome sequencing followed by genotyping of 56 informative relatives in the 4 families suggests that the phenotype is due to homozygosity for KREMEN1 p.F209S (c.626 T4C) on chromosome 22 at g.29,521,399 (hg19). The variant occurs in the highly conserved extracellular WSC domain of KREMEN1, which is known to be a high affinity receptor of Dickkopf-1, a component of the Dickkopf-Kremen-LRP6 complex, and a potent regulator of Wnt signaling. The Wnt signaling pathway is critical to development of ectodermal structures. Mutations in WNT10A, LRP6, EDA, and other genes in this pathway lead to tooth agenesis with or without other ectodermal anomalies. Our results implicate KREMEN1 for the first time in a human disorder and provide additional details on the role of the Wnt signaling in ectodermal and dental development.

Novel compound heterozygous mutations in KREMEN1 confirm it as a disease gene for ectodermal dysplasia

“…Comparing our patients with the Palestinian patients, the absence of permanent upper lateral incisors and lower anterior teeth, and presence of upper central incisors, were found in all seven patients. 1 This aberrant dental pattern could be a pathognomonic feature of KREMEN1 mutations. More individuals with KREMEN1 mutations are needed to substantiate this observation.…”

“…Dear Editor , Ectodermal dysplasia (ED) is a heterogeneous group of disorders caused by mutations in at least 13 genes. Recently, a study reported Palestinian patients with ED from consanguineous families with a homozygous mutation in KREMEN1 and proposed it to be a causative gene for the autosomal recessive ED 13, hair/tooth type (ECTD13; OMIM 617392) …”

“…Issa et al . proposed, for the first time, that KREMEN1 was another disease gene for ED . However, as no functional studies have been performed for the p.F209S mutation, the pathogenicity and causative role of KREMEN1 in ED are unconfirmed.…”

“…Recently, a study reported Palestinian patients with ED from consanguineous families with a homozygous mutation in KREMEN1 and proposed it to be a causative gene for the autosomal recessive ED 13, hair/tooth type (ECTD13; OMIM 617392). 1 A Thai family, parents and two children affected with ED, was recruited. The study was exempted from review by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University (IRB584/60).…”

“…Issa et al proposed, for the first time, that KREMEN1 was another disease gene for ED. 1 However, as no functional studies have been performed for the p.F209S mutation, the pathogenicity and causative role of KREMEN1 in ED are unconfirmed. More recently, homozygous p.T49R and p.F258_P259del were detected as likely to be pathogenic in two Turkish white probands with mild features of ED.…”