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NUCLEOLUS AND NEURAL PROGENITOR PROTEIN; NEPRO

NUCLEOLUS AND NEURAL PROGENITOR PROTEIN; NEPRO

Alternative titles; symbolsCHROMOSOME 3 OPEN READING FRAME 17; C3ORF17HGNC Approved Gene Symbol: NEPROCytogenetic location: 3q13.2 Genomic coordinates (GRCh3...

Alternative titles; symbols

  • CHROMOSOME 3 OPEN READING FRAME 17; C3ORF17

HGNC Approved Gene Symbol: NEPRO

Cytogenetic location: 3q13.2 Genomic coordinates (GRCh38): 3:113,002,443-113,019,720 (from NCBI)

▼ Description
In developing neocortex, neural progenitor cells (NPCs) produce projection neurons of the 6 cortical layers in a temporal order. Maintenance of the NPC pool is essential for generation of distinct types of neurons at the required time. NEPRO is required for maintenance of cortical NPCs in the undifferentiated state during early cortical development (Muroyama and Saito, 2009).

▼ Cloning and Expression
Muroyama and Saito (2009) cloned mouse Nepro and identified orthologs in vertebrates, including human, but not in invertebrates. The deduced mouse and human proteins contain 564 and 567 amino acids, respectively. Both contain a conserved N-terminal QVEQC motif, followed by a hydrophobic region, a nuclear localization signal, and a C-terminal DDIDDIF motif. In situ hybridization of mouse embryos detected faint Nepro expression in the ventricular zone of the forebrain at embryonic day 9.5 (E9.5). Nepro was visible at E10.5 to E12.5 before declining and becoming almost absent by E15.5. Epitope-tagged Nepro localized to nucleus at E13.5.

▼ Mapping
Hartz (2016) mapped the NEPRO gene to chromosome 3q13.2 based on an alignment of the NEPRO sequence (GenBank AL117573) with the genomic sequence (GRCh38).

▼ Gene Function
By in vivo electroporation in mouse embryos, Muroyama and Saito (2009) found that overexpression of fluorescence-tagged Nepro at E13.5 inhibited NPC differentiation and reduced the number of neurons that migrated to the cortical plate. The majority of Nepro-positive cells remained in the ventricular zone. Overexpression of Nepro in NPCs at E15.5 had no effect on neuronal migration, suggesting that Nepro inhibits neuronal differentiation only at early stages. In contrast, knockdown of Nepro at E11.5 reduced the number of neurons at the ventricular zone and increased the number of neurons at the cortical plate. Mutation analysis revealed that the C-terminal half of Nepro was required to inhibit neuronal differentiation. Nepro was activated by the constitutively active form of Notch (see 190198), which inhibits neuronal differentiation, but not by Hes genes (see 139605), which also suppress neuronal differentiation. Inhibition of Notch activity reduced mRNA levels of both Nepro and Hes5 (607348), suggesting that Nepro, like Hes genes, is activated downstream of canonical Notch signaling. Overexpression and inhibitor studies showed that both Nepro and Hes were necessary for maintenance of NPCs during early mouse cortical development.

▼ Molecular Genetics
By autozygome/exome analysis in a cohort of 31 Saudi Arabian families with dysmorphology syndromes that did not appear to fit a previously recognized syndrome, Shaheen et al. (2016) identified a sister and brother with a skeletal dysplasia, anauxetic dysplasia-3 (ANXD3; 618853), who were homozygous for a missense mutation in the NEPRO gene (R94C; 617089.0001).

From a cohort of 411 skeletal dysplasia patients from 288 families, Maddirevula et al. (2018) identified homozygosity for the R94C missense mutation in the NEPRO gene in 2 Arab brothers who exhibited skeletal dysplasia that they stated was identical to that of the sibs reported by Shaheen et al. (2016). Haplotype analysis confirmed the founder nature of the variant.

By whole-exome sequencing in a 13-year-old Indian girl with severe short stature and skeletal dysplasia, Narayanan et al. (2019) identified homozygosity for a missense mutation in the NEPRO gene (L145F; 617089.0002). Her second-cousin parents were heterozygous for the mutation, which was not found an in-house exome database or in public variant databases. The authors noted that both the R94C and L145F variants occurred in the same domain (DUF4477) of the NEPRO protein.

▼ Animal Model
Hashimoto et al. (2015) found that Nepro was indispensable for preimplantation development in mice, as Nepro -/- embryos died before implantation. Nepro played a role in formation of nucleolus precursor bodies and nucleolus, and deletion of Nepro in mice caused abnormal ribosome biogenesis. Loss of Nepro increased the amount of mitochondria-associated p53 (TP53; 191170) protein, leading to cytochrome c release from mitochondria, caspase activation, apoptosis, and death of Nepro -/- embryos.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 ANAUXETIC DYSPLASIA 3
NEPRO, ARG94CYS
In a Saudi Arabian sister and brother (family 16, patients 15DG0764 and 15DG0765) with anauxetic dysplasia-3 (ANXD3; 618853), Shaheen et al. (2016) identified homozygosity for a c.280C-T transition (c.280C-T, NM_015412.3) in the NEPRO gene, resulting in an arg94-to-cys (R94C) substitution. Their unaffected first-cousin parents were each heterozygous for the mutation.

In 2 brothers from a consanguineous Arab family (family 1, patients 15DG2238 and 15DG2239) with a skeletal dysplasia that the authors stated was identical to that of the sibs reported by Shaheen et al. (2016), Maddirevula et al. (2018) identified homozygosity for the R94C mutation in the NEPRO gene. Their consanguineous parents were unaffected, but segregation analysis was not reported. Haplotype analysis confirmed the founder nature of the variant.

.0002 ANAUXETIC DYSPLASIA 3
NEPRO, LEU145PHE
In a 13-year-old Indian girl (P1) with anauxetic dysplasia-3 (ANXD3; 618853), Narayanan et al. (2019) identified homozygosity for a c.435G-C transversion (c.435G-C, NM_015412.4) in exon 4 of the NEPRO gene, resulting in a leu145-to-phe (L145F) substitution at a highly conserved residue. Her second-cousin parents were heterozygous for the mutation, which was not found in 576 in-house exomes from 438 Indian families with rare mendelian disorders, or in the ExAC or gnomAD databases.

Tags: 3q13.2