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A Splice Site Mutation Associated with Congenital CD59 Deficiency.

ABSTRACT: Congenital CD59 deficiency is a recently described rare autosomal recessive disease associated with CD59 gene mutations that lead to deficient or dysfunctional CD59 protein on the cell surface. The disease is characterized by the early onset of chronic hemolysis, relapsing peripheral demyelinating neuropathy, and recurrent ischemic strokes. To date, there are 14 patients with 4 exon mutations reported globally. A young boy with early onset peripheral neuropathy and atypical hemolytic uremic syndrome is presented. Next-generation sequencing (NGS) identified a homozygous splice site variant in intron 1 of the CD59 gene (c.67 + 1G > T). This variant alters a consensus donor splicing site. Quantitative reverse transcription PCR showed that CD59 mRNA expression in the patient is significantly reduced to 0.017-fold compared to the controls. Flow cytometry showed the lack of CD59 protein on the surface of the patient’s red blood cells. This variant is the first splice site mutation reported to be associated with congenital CD59 deficiency.

SUBMITTER: Chai JN

PROVIDER: S-EPMC9222317 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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A Splice Site Mutation Associated with Congenital CD59 Deficiency.

Chai Jiani N JN Azad Abul Kalam AK Kuan Kevin K Guo Xiaoling X Wang Yanhua Y

Hematology reports 20220527 2

Congenital CD59 deficiency is a recently described rare autosomal recessive disease associated with CD59 gene mutations that lead to deficient or dysfunctional CD59 protein on the cell surface. The disease is characterized by the early onset of chronic hemolysis, relapsing peripheral demyelinating neuropathy, and recurrent ischemic strokes. To date, there are 14 patients with 4 exon mutations reported globally. A young boy with early onset peripheral neuropathy and atypical hemolytic uremic synd ...[more]

PMID: 35735736

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Project description:PurposeLeber congenital amaurosis (LCA) is one of the most common causes of hereditary blindness in infants. To date, mutations in 13 known genes and at two other loci have been implicated in LCA causation. An examination of the known genes highlights several processes which, when defective, cause LCA, including photoreceptor development and maintenance, phototransduction, vitamin A metabolism, and protein trafficking. In addition, it has been known for some time that defects in sensory cilia can cause syndromes involving hereditary blindness. More recently evidence has come to light that non-syndromic LCA can also be a "ciliopathy."MethodsHere we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene. Homozygosity mapping was done using Affymetrix 10K Xba I Gene Chip and a 24.5cM region on chromosome 6 (6q12- q16.3) was identified to be significantly homozygous. The LCA5 gene on this region was sequenced and cDNA sequencing also done to characterize the mutation.ResultsA c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs. Since there is a second consensus splice donor sequence 5 bp into the adjacent intron, this mutation results in a transcript with a 5 bp insertion of intronic sequence, leading to a frameshift and premature truncation.ConclusionsWe report a missense mutation functionally altering the splice donor site and leading to a truncated protein. This is the second report of LCA5 mutations causing LCA. It may also be significant that one affected child died at eleven months of age due to asphyxia during sleep. To date the only phenotype unambiguously associated with mutations in this gene is LCA. However the LCA5 gene is known to be expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes. The cause of death in this child may therefore imply that LCA5 mutations can in fact cause a wider spectrum of phenotypes including respiratory disease.

Dataset Information

A Splice Site Mutation Associated with Congenital CD59 Deficiency.

Publications

A Splice Site Mutation Associated with Congenital CD59 Deficiency.

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