title: 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.
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.|Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Barraza-García
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.|Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: C I
authors.initials: CI
authors.lastname: Rivera-Pedroza
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.|Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Hisado-Oliva
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.|Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Belinchón-Martínez
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.|Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.|Department of Pediatric Endocrinology, Hospital Universitario Infanta Leonor, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Sentchordi-Montané
authors.affiliation: Department of Endocrinology, Royal Brisbane and Women's Hospital, Herston, Australia.
authors.forename: E L
authors.initials: EL
authors.lastname: Duncan
authors.affiliation: Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: G R
authors.initials: GR
authors.lastname: Clark
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Del Pozo
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: K
authors.initials: K
authors.lastname: Ibáñez-Garikano
authors.affiliation: Radiology Department, Sheffield Children's Hospital NHS Foundation Trust and Academic Unit of Child Health, University of Sheffield, Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Offiah
authors.affiliation: Pediatric Endocrinology Unit, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Prieto-Matos
authors.affiliation: Department of Medical Genetics, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes-Sorbonne Paris Cité University, AP-HP, Institut Imagine and Hôpital Universitaire Necker-Enfants Malades, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.|Multidisciplinary Skeletal dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: K E
authors.identifier: http://orcid.org/0000-0002-5816-7044
authors.initials: KE
authors.lastname: Heath
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004392:Dwarfism / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D009139:Musculoskeletal Abnormalities / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C490350:POP1 protein, human; C544035:RMRP non-coding RNA, human; D062085:RNA, Long Noncoding; D012261:Ribonucleoproteins
keywords: POP1; RMRP; anauxetic dysplasia; bone; skeletal dysplasia