A number sign (#) is used with this entry because of evidence that cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-1 (CHINE1) is caused by hemizygous or heterozygous mutation in the DKC1 gene (300126) on chromosome Xq28. One such family has been reported.

Mutation in the DKC1 gene can also cause X-linked dyskeratosis congenita (DKCX; 305000).

Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-1 (CHINE1) is an X-linked syndromic disorder that is phenotypically more severe in males than females. Affected males present with the full constellation of symptoms in early infancy, resulting in death in early childhood. Affected females develop early-onset hearing impairment, often with early-onset cataracts, but only rarely have nephrotic syndrome or proteinuria; they do not have enterocolitis. The variable manifestations in females may be influenced by skewed X-inactivation. Telomeres are shortened, but classic mucocutaneous features of DKCX are not typically observed. CHINE1 is due to a ribosomal pseudouridylation defect (Balogh et al., 2020).

See also CHINE2 (620425), caused by mutation in the NOP10 gene (606471).

Balogh et al. (2020) reported a large multigenerational family (family A) in which 6 males presented in infancy with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis resulting in death in early childhood in all patients. Some had failure to thrive and 3 had bone marrow failure. Seven females in this family, ranging from 11 to 60 years of age, had early-onset hearing impairment. Of these females, 5 also had early-onset cataracts, including 3 with retinitis pigmentosa. One of the females developed nephrotic syndrome at 2 years of age, and another showed nonnephrotic proteinuria. Some of the affected females had a history of failure to thrive. In addition, 2 females had microphthalmia, 2 had mandibular and maxillary hypoplasia, and 2 had cerebellar atrophy and pineal hypoplasia. Only the male patients developed enterocolitis. Affected females showed telomere shortening in the absence of classic mucocutaneous features of dyskeratosis congenita (nail dystrophy and leukoplakia), although 1 had mild hyperkeratosis. Balogh et al. (2020) noted that the affected males in this family died before the age of typical onset of DKC symptoms. Genetic testing was performed on 1 of the deceased males and in 6 of the affected females. The transmission pattern was consistent with X-linked inheritance, with the disorder being much more severe in males compared to the females.

The transmission pattern of CHINE1 in family A reported by Balogh et al. (2020) was consistent with X-linked inheritance and incomplete penetrance in carrier females. The most severely affected female (IV:4) in this family showed highly skewed X inactivation with preference for the mutant allele.

In 1 affected male and 6 affected females from a large multigenerational family (family A) with CHINE1, Balogh et al. (2020) identified a hemizygous or heterozygous missense mutation in the DKC1 gene (E206K; 300126.0016). Two unaffected females also carried the mutation, indicating incomplete penetrance in females. The mutation occurred at a conserved residue in the DKC1-NOP10 (606471) interface in a region distinct from those implicated in DKCX. Molecular modeling and in vitro studies showed that the mutation altered the hydrogen binding between dyskerin and NOP10, disrupted the catalytic pseudouridylation site, and altered the pseudouridylation capacity of the snoRNP complex. Peripheral blood cells from the most severely affected female in this family (IV:4) showed a pseudouridylation defect of 18S rRNA that was not observed in patient fibroblasts, suggesting a tissue-specific effect. Expression of the E206K mutation in dkc1-null zebrafish was unable to fully rescue the developmental phenotype, indicating that it is a hypomorphic mutation (see ANIMAL MODEL). 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 the phenotype.

Balogh et al. (2020) found that knockdown of the dkc1 gene in zebrafish resulted in death at 5 days postfertilization. Ocular sections of dkc1-null larvae showed opaque lenses resembling cataracts, increased neuroepithelial progenitor cells, and retinal cell proliferation indicative of a cell-cycle defect. Mutant animals showed microphthalmia, impaired development of the inner ear and intestinal compartments of the gut, hypoplastic pronephros with reduced podocytes, hematopoietic defects, defective jaw-cartilage development, and a disorganized pineal gland. Telomere shortening was not observed. Expression of wildtype human DKC1 could rescue the phenotypes, but expression of the E206K variant only showed limited rescue. There was also evidence of impaired pseudouridylation of 18S rRNA and defects in ribosomal biogenesis and function.