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

Abstract

Processing of Precursor 1 (POP1) is a large protein common to the ribonuclease‐mitochondrial RNA processing (RNase‐MRP) and RNase‐P (RMRP) endoribonucleoprotein complexes. Although its precise function is unknown, it appears to participate in the assembly or stability of both complexes. Numerous RMRP mutations have been reported in individuals with cartilage‐hair hypoplasia (CHH) but, to date, only three POP1 mutations have been described in two families with features similar to anauxetic dysplasia (AD). We present two further individuals, one with severe short stature and a relatively mild skeletal dysplasia and another in whom AD was suspected. Biallelic POP1 mutations were identified in both. A missense mutation and a novel single base deletion were detected in proband 1, p.[Pro582Ser]:[Glu870fs*5]. Markedly reduced abundance of RMRP and elevated levels of pre5.8s rRNA was observed. In proband 2, a homozygous novel POP1 mutation was identified, p.[(Asp511Tyr)];[(Asp511Tyr)]. These two individuals show the phenotypic extremes in the clinical presentation of POP1‐dysplasias. Although CHH and other skeletal dysplasias caused by mutations in RMRP or POP1 are commonly cited as ribosomal biogenesis disorders, recent studies question this assumption. We discuss the past and present knowledge about the function of the RMRP complex in skeletal development.

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

“…All probands were analysed using a custom‐designed skeletal dysplasia next‐generation sequencing (NGS) panel, SKELETALSEQ.V3‐6 (n = 315‐368 genes) and sequenced on a MiSeq/NextSeq sequencer (Illumina, San Diego, CA, USA). Bioinformatic analyses were conducted as previously described . Conservation, pathogenicity prediction analysis and population frequences of the identified ACAN variants were carried out using CADD V1.3 (http://cadd.gs.washington.edu/), GerpRS (http://mendel.stanford.edu/SidowLab/downloads/gerp/) and Alamut V2.10 (Interactive Biosoftware, France) and gnomAD database (http://gnomad.broadinstitute.org).…”

“…Aggrecan consists of an N‐terminal domain, two globular domains (G1 and G2), two interglobular domains (CS and KS attachment regions), a selectin‐like domain (G3) and a C‐terminal domain . Mutations are located throughout the protein, and no genotype‐phenotype correlations have been observed .…”

The novel R211Q POP1 homozygous mutation causes different pathogenesis and skeletal changes from those of previously reported POP1‐associated anauxetic dysplasia

“…The use of this “genotype first” approach has led to the recognition of a new candidate gene, POP1 , as a cause of a peculiar type of skeletal dysplasia with severe short stature (Barraza‐García et al, ; Glazov et al, ). Processing of Precursor RNA 1 protein (POP1) is the largest protein component of both RNase P and RNase MRP (the mitochondrial RNA processing ribonuclease) complexes.…”

“…Both are RNA‐based endonucleases essential for the viability of eukaryotic cells (Lygerou, Mitchell, Petfalski, Seraphin, & Tollervey, ; Schmitt & Clayton, ). The only five patients with POP1 mutations reported so far (Barraza‐García et al, ; Elalaoui et al, ; Glazov et al, ), manifested anauxetic dysplasia (AnD); an autosomal recessive (AR) spondylo‐epi‐metaphyseal dysplasia characterized by extremely short stature (Menger, Mundlos, Becker, Spranger, & Zabel, ), with variable severity of involvement of the skull, spine, epiphyses, and metaphyses of long bones. Other AnD cases were caused by mutations in RMRP , the untranslated RNA moiety of the RNase MRP complex (Thiel et al, ).…”

First case of compound heterozygous BHLHA9 variants in mesoaxial synostotic syndactyly with phalangeal reduction

“…Mutation screening was performed in the proband using a custom‐designed skeletal dysplasia NGS gene panel (SKELETALSEQ.V8, n = 419 genes Roche Nimblegen, Madison, WI) and sequenced on a NextSeq sequencer (Illumina, San Diego, CA). Bioinformatic analysis and variant calling was performed as previously described (Barraza‐García et al, ; Sentchordi‐Montané et al, ). The identified variants were subsequently validated by Sanger sequencing, along with family analysis.…”