A number sign (#) is used with this entry because of evidence that cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-2 (CHINE2) is caused by homozygous mutation in the NOP10 gene (606471) on chromosome 15q14. One such family has been reported.

Biallelic mutation in the NOP10 gene also causes autosomal recessive dyskeratosis congenita-1 (DKCB1; 224230).

Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-2 (CHINE2) is an autosomal recessive syndromic disorder characterized by onset of this constellation of features in infancy, resulting in death in early childhood. Telomeres are shortened, but classic mucocutaneous features of DKCB1 are not typically observed. CHINE2 is due to a ribosomal pseudouridylation defect (Balogh et al., 2020).

See also CHINE1 (301108), caused by mutation in the DKC1 gene (300126).

Balogh et al. (2020) reported a large consanguineous family (family B) in which 2 female infants presented at birth with sensorineural hearing impairment. Other features included cataracts, nephrotic syndrome associated with focal segmental glomerulosclerosis (FSGS) and mesangial proliferative glomerulonephritis (MPGN) on biopsy, and enterocolitis. Brain imaging of 1 patient showed cerebellar hypoplasia and hypomyelination. Laboratory studies showed shortened telomeres. Classic mucocutaneous features of dyskeratosis congenita were not observed, although 1 patient had mild dyskeratosis. Both girls died at 3 years of age. The mother of 1 of the patients had hearing impairment.

The transmission pattern of CHINE2 in family B reported by Balogh et al. (2020) was consistent with autosomal recessive inheritance.

In 2 girls from a highly consanguineous family (family B) with CHINE2, Balogh et al. (2020) identified a homozygous missense mutation in the NOP10 gene (T16M; 606471.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not present in the general population. The mother of one of the affected girls had hearing impairment, but her genotype was not noted. Patient cells showed a reduced level of the mutant NOP10 protein, suggesting a possible effect on protein stability. The mutation occurred in the DKC1 (300126)-NOP10 interface in a region distinct from those implicated in dyskeratosis congenita. Although the binding interaction with DKC1 was maintained, molecular modeling and in vitro studies showed that the T16M mutation altered the hydrogen binding between NOP10 and DKC1, disrupted the catalytic pseudouridylation site, and altered the pseudouridylation capacity of the snoRNP complex. Peripheral blood cells from 1 of the patients showed a pseudouridylation defect of 18S rRNA. Despite the finding of shortened telomeres in the affected females, the authors concluded that a pseudouridylation defect causing ribosomal dysfunction is the primary driver of this unique phenotype.