Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function

Abstract

Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals from 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1 mutations, 5 novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. In four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S mutation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of

Mutational spectrum of Korean patients with corneal dystrophy

“…All detected missense mutations occurred in a prenyltransferase domain from residues 58 to 333 (37) and were located in regions where previously reported UBIAD1 mutations are clustered. However, the p.Asn102Ser mutation, previously reported as a mutation hot spot (38), was not identified in this study.…”

Functional study of SCCD pathogenic gene UBIAD1 (Review)

“…Similarly, the occurrence of SCCD is higher in European and North American countries compared with other countries and regions associated with this gene defect, including Asia and Africa. Prevalence of SCCD is also reported in the Chinese Han and Japanese populations ( 22 , 36 , 38 , 39 ). To further understand this gene, Dong et al ( 40 ) constructed an SCCD mouse model with N100S mutation by CRISPR-Cas9 gene editing to further clarify the pathogenesis and treatment of SCCD.…”

“…The present review has investigated 28 point mutations of UBIAD1 that cause SCCD through a literature search and the details are demonstrated in Table I . The mutation hot spot in UBIAD1 was on 102 (N102S), which had been demonstrated in a number of SCCD-affected families ( 7 – 9 , 22 , 33 – 38 ). Similarly, the occurrence of SCCD is higher in European and North American countries compared with other countries and regions associated with this gene defect, including Asia and Africa.…”