Further evidence of POP1 mutations as the cause of anauxetic dysplasia

Abstract

Anauxetic dysplasia (AAD, OMIM 607095) is a rare skeletal dysplasia inherited as an autosomal recessive trait, which is caused by mutations in RMRP and allelic to a more common disorder, cartilage hair hypoplasia (CHH). CHH is a multi-system disorder with a variety of extraskeletal changes. Whereas AAD is a bone-restricted disorder with a more severe skeletal phenotype: affected individuals are extremely short and complicated by orthopedic morbidity, and the radiological changes include modification of the vertebral bodies and epiphyseal dysplasia of the hip, as well as generalized metaphyseal dysplasia and severe brachydactyly. Recently, genetic heterogeneity for AAD was proposed, because a familial case (two affected sibs) with an AAD-identical phenotype had compound heterozygous mutations in POP1, encoding a molecule functionally related to the gene product of RMRP. We report here a 5-year-old boy with the same phenotype born to a consanguineous couple. We identified a novel homozygous POP1 mutation (c.1744C>T, p.P582S) in the boy and the heterozygosity in the parents. It may be rational to coin the POP1-associated skeletal phenotype AAD type 2. © 2016 Wiley Periodicals, Inc.

Broadening the phenotypic spectrum of POP1‐skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia

“…Proband 1 is a compound heterozygote for a missense and a frameshift mutation. Interestingly, the p.Pro582Ser mutation has been recently reported in homozygosity in a Moroccan individual with AD‐like features . As proband 1 is also of Moroccan origin, the two individuals probably share a common ancestor.…”

“…Thus, to date, five different POP1 mutations have been reported in five individuals from four families (this study, ) (Fig. ).…”

“…], red arrows [p.( Pro582Ser );( Pro582Ser ), Ref. ]. Orange box: POP1 domain; blue box: POPLD domain.…”

“…Both variants are absent from population databases. The missense variant has been recently reported in homozygosity in an individual from Morrocco . It affects a highly conserved amino acid and in silico pathogenicity predictions classify the variant as highly deleterious.…”

“… Table S2: Details of the Processing of Precursor 1 ( POP1 ) mutations identified in this study and those previously reported . The conservation, frequency in the population datasets (Exome Aggregation Consortium, ExAC ; Exome Sequencing Project, ESP ; and Kaviar) and in silico predictions are documented for each mutation.…”