title: Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator.
abstract: The growth of an individual is deeply influenced by the regulation of cell growth and division, both of which also contribute to a wide variety of pathological conditions, including cancer, diabetes, and inflammation. To identify a major regulator of human growth, we performed positional cloning in an autosomal recessive type of profound short stature, anauxetic dysplasia. Homozygosity mapping led to the identification of novel mutations in the RMRP gene, which was previously known to cause two milder types of short stature with susceptibility to cancer, cartilage hair hypoplasia, and metaphyseal dysplasia without hypotrichosis. We show that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity is explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the cartilage hair hypoplasia founder mutation affects both pathways intermediately, anauxetic dysplasia mutations do not affect B-cyclin messenger RNA (mRNA) levels but do severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA while allowing normal mRNA processing and, therefore, genetically separate the different functions of RNase MRP.
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nurnberg, Erlangen, Germany.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Thiel
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Kelly
authors.initials: K
authors.lastname: Salinas
authors.forename: Erich
authors.initials: E
authors.lastname: Gebhart
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Jürgen
authors.initials: J
authors.lastname: Spranger
authors.forename: Dietmar
authors.initials: D
authors.lastname: Müller
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schmitt
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
mesh_terms: D001842:Bone and Bones / Q000002:abnormalities*; D002356:Cartilage / Q000002:abnormalities*; D002453:Cell Cycle / Q000235:genetics; D004722:Endoribonucleases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006130:Growth Disorders / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D012313:RNA / Q000378:metabolism
chemical_list: D012313:RNA; D004722:Endoribonucleases