Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis

Abstract

Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange‐Nielsen Syndrome and Romano‐Ward Syndrome

“…Subsequently, an additional nineteen chromosome 21q markers were genotyped to refine an interval on chromosome 21q22.12 to 17.6 Mb, including 127 annotated genes and pseudogenes. The exons and flanking intronic DNA were Sanger sequenced for CLDN14 and TMPRSS3 , two genes associated unambiguously with congenital nonsyndromic sensorineural hearing loss (Scott et al., ; Wilcox et al., ), as well as TSPEAR , a third gene also located in this 21q interval, but with a debatable association with deafness (Delmaghani et al., ; Peled et al., ) (Figure b). Because no likely pathogenic variants were uncovered in the coding sequence of these three chr21q‐linked genes, a genomic DNA sample from affected individual V:4 of family PKDF461 was submitted to the New York Genome Center (NYGC) for whole genome sequencing at a mean genome‐wide coverage of 30× depth.…”

“…The evidence supporting a recessive variant (c.1726_1728delGTCinsTT) of TSPEAR (light blue) associated with deafness (Delmaghani et al., ) has been called into question. Homozygosity for this variant was found in normal hearing individuals (Peled et al., ). (c) Representative chromatograms of the genomic DNA sequences of three family members (V:2, IV:6, and V:4) who are homozygous for the reference allele, and heterozygous and homozygous for the KCNE1 c.138C>A variant.…”

“…Microsatellite D21S1411 is the distal boundary while SNP rs2829553 is the proximal linkage boundary of a 17.6 Mb homozygous interval shared among the four affected individuals of family PKDF461 (Figure b). This interval includes two previously reported nonsyndromic deafness loci, DFNB8 / B10 ( TMPRSS3 ) (Veske et al., ) and DFNB29 ( CLDN14 ) (Ben‐Yosef et al., ; Wilcox et al., ) and a disputed third deafness locus DFNB98 ( TSPEAR ) (Delmaghani et al., ; Peled et al., ). Sanger sequencing of all annotated exons of TMPRSS3 , CLDN14 , and TSPEAR did not reveal a coding or splice site variant that might explain the hearing loss segregating in family PKDF461.…”

Growth factor and receptor malfunctions associated with human genetic deafness

“…This appears to be the case for variants in MYO1A, MYO1C, MYO1F and TSPEAR reported in deafness. 9,10 Here, we highlight three examples where there is robust data from human genetics and supporting data from animal models that both the receptor and its ligand, and other molecules in their signaling pathways, are necessary for hearing. When a ligand binds its receptor, a conformational change occurs in the receptor, initiating a signal propagated through second messengers.…”

Novel TSPEAR mutations in non‐syndromic oligodontia

“…Recently, mutations in a novel gene, thrombospondin-type laminin G domain and EAR repeats (TSPEAR), have been identified to cause a novel form of ectodermal dysplasia in three families (Peled et al, 2016). Subsequently, two additional tooth agenesis families were reported to be caused by recessive homozygous TSPEAR mutations and interestingly, a family with homozygous c.1877T>C, p.(Phe-626Ser) mutation had non-syndromic oligodontia (Du et al, 2018).…”