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

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. K E Y W O R D S cartilage hair hypoplasia, metaphyseal dysplasia, NEPRO, ribosomal biogenesis, RMRP

Expanding the phenotype of anauxetic dysplasia caused by biallelic NEPRO mutations: A case report

“…All ANXD types may also exhibit an extraskeletal phenotype that includes motor and cognitive developmental delays and frequent airway infections, as seen in our patient (Akgün-Do gan et al, 2018;Barraza-García et al, 2017;Narayanan et al, 2019). In contrast to most previously reported patients, our patient did not exhibit skin laxity, but this may simply be masked by the ichthyotic epidermal hyperproliferation.…”

“…These four patients were born of consanguineous parents of Arabic descent, as was our patient, further suggesting that this variant is an Arabic founder mutation. In the fifth patient, Narayanan et al (2019) found a different homozygous NEPRO variant, c.435G > C, p.(Leu145Phe), and provided in silicio evidence for decreased stability of both mutant proteins.…”

“…Together with ANXD1 and ANXD2, ANXD3 is on the severe skeletal end of the CHH‐AD spectrum and is clinically characterized by severe short stature, brachydactyly, skin laxity, and joint hypermobility and dislocations. Radiographic findings tend to be variable in all ANXD types, but common findings are ovoid‐shaped vertebrae with platyspondyly, hypoplastic or squared ilia, hypoplastic acetabulae, small femoral epiphyses with narrow femoral necks, irregular metaphyses and short and broad metacarpals and phalanges (Barraza‐García et al, 2017; Narayanan et al, 2019). In ANXD, in contrast to MDWH and CHH, there are no extraskeletal features such as immunodeficiency, anemia, and intestinal manifestations and no predisposition to malignancies.…”

“…In ANXD, in contrast to MDWH and CHH, there are no extraskeletal features such as immunodeficiency, anemia, and intestinal manifestations and no predisposition to malignancies. To date, only five ANXD3 patients have been described, from three different families (Maddirevula et al, 2018; Narayanan et al, 2019; Shaheen et al, 2016). Here, we report a new patient with biallelic NEPRO variants and additional features that broaden the phenotypic features of ANXD3.…”

Immunodeficiency in cartilage‐hair hypoplasia: Pathogenesis, clinical course and management

“…Interestingly, variants in POP1 , encoding one of the proteins in the RNase MRP complex (hPOP1, Figure 1), have been described in patients with skeletal dysplasia and decreased peripheral blood mononuclear cell proliferation ability 21 . Furthermore, variants in NEPRO , encoding nucleolus and neural progenitor protein known to interact with multiple subunits of the RNase MRP complex, have been recently described in a patient with skeletal dysplasia and hair hypoplasia 22 . Further studies are needed to test the hypothesis of whether allelic differences in POP1 and genes encoding other proteins of the RNase MRP complex or interacting proteins can be responsible for the variability in CHH clinical phenotype.…”