An emerging ribosomopathy affecting the skeleton due to biallelic variations in NEPRO

Am J Med Genet A. 2019 Sep;179(9):1709-1717. doi: 10.1002/ajmg.a.61267. Epub 2019 Jun 27.

Abstract

Cartilage hair hypoplasia (CHH), anauxetic dysplasia 1, and anauxetic dysplasia 2 are rare metaphyseal dysplasias caused by biallelic pathogenic variants in RMRP and POP1, which encode the components of RNAse-MRP endoribonuclease complex (RMRP) in ribosomal biogenesis pathway. Nucleolus and neural progenitor protein (NEPRO), encoded by NEPRO (C3orf17), is known to interact with multiple protein subunits of RMRP. We ascertained a 6-year-old girl with skeletal dysplasia and some features of CHH. RMRP and POP1 did not harbor any causative variant in the proband. Parents-child trio exomes revealed a candidate biallelic variant, c.435G>C, p.(Leu145Phe) in NEPRO. Two families with four affected individuals with skeletal dysplasia and a homozygous missense variant, c.280C>T, p.(Arg94Cys) in NEPRO, were identified from literature and their published phenotype was compared in detail to the phenotype of the child we described. All the five affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. Protein modeling and stability prediction showed that the mutant protein has decreased stability. Both the reported variants are in the same domain of the protein. Our report delineates the clinical and radiological characteristics of an emerging ribosomopathy caused by biallelic variants in NEPRO.

Keywords: NEPRO; RMRP; cartilage hair hypoplasia; metaphyseal dysplasia; ribosomal biogenesis.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Apoptosis Regulatory Proteins / genetics
  • Child
  • Dwarfism / genetics*
  • Dwarfism / pathology
  • Female
  • Glycoside Hydrolases / genetics*
  • Hair / abnormalities
  • Hair / pathology
  • Hirschsprung Disease / genetics
  • Hirschsprung Disease / pathology
  • Humans
  • Multiprotein Complexes / genetics
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Osteochondrodysplasias / congenital
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Pedigree
  • Phenotype
  • Primary Immunodeficiency Diseases / genetics
  • Primary Immunodeficiency Diseases / pathology
  • RNA, Long Noncoding / genetics
  • Repressor Proteins / genetics*
  • Ribonucleoproteins / genetics
  • Ribosomes / genetics
  • Ribosomes / immunology*
  • Ribosomes / pathology
  • Skeleton / metabolism
  • Skeleton / pathology

Substances

  • Apoptosis Regulatory Proteins
  • Multiprotein Complexes
  • NEPRO protein, human
  • Nerve Tissue Proteins
  • POP1 protein, human
  • RMRP non-coding RNA, human
  • RNA, Long Noncoding
  • Repressor Proteins
  • Ribonucleoproteins
  • Glycoside Hydrolases
  • endorhamnosidase

Supplementary concepts

  • Anauxetic dysplasia
  • Cartilage-hair hypoplasia
  • Pyle disease