Abstract
Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia, caused by defects in the steroidogenic acute regulatory protein (STAR). The STAR p.Q258* mutation is the most common mutation in China, Japan and Korea, suggesting a founder effect. This study aimed to investigate the phenotypic and mutation spectrum of STAR defects and identify the founder effect of the p.Q258* mutation in Korean patients with CLAH. For 45 patients from 42 independent pedigrees, haplotype analysis was performed in 10 unrelated trio families, including patients with the p.Q258* mutation whose DNA samples were available, using 1,972 single nucleotide polymorphism (SNP) and six short tandem repeat markers. An Illumina Infinium® Human Omni2.5-8 v1.3 performed the SNP genotyping. Among 84 alleles from 42 unrelated families, mutation p.Q258* was found in 74 alleles (88.1%) from 41 families. A shared haplotype was identified in 17 of 20 alleles from 10 patients (size, 198 kb). The age of the founder mutation was estimated as 4,875 years (95% credible set: 3,575–7,925 years), assuming an intergenerational time interval of 25 years. The STAR p.Q258* mutation is the most common in Korean patients with CLAH, suggesting a founder effect. The age of the mutation corresponds with the time when the Korean people settled in the Korean peninsula. The high prevalence of p.Q258* in Japan and China also suggests a founder effect in Asian countries.
Highlights
Congenital lipoid adrenal hyperplasia (CLAH, OMIM #201710) is a rare autosomal recessive disorder caused by defects in the steroidogenic acute regulatory (STAR) protein [1,2]
One genetic male, who was compound heterozygous for p.Q258* and p.R272H, demonstrated perfect male external genitalia and have been raised as a boy
The other two genetic females, who were both compound heterozygous for p.Q258* and p.V187M, showed skin hyperpigmentation and hyponatremia at the age of 1.2 years and 2.8 years, respectively
Summary
Congenital lipoid adrenal hyperplasia (CLAH, OMIM #201710) is a rare autosomal recessive disorder caused by defects in the steroidogenic acute regulatory (STAR) protein [1,2]. The defects in the synthesis of all adrenal steroid hormones caused by STAR mutations result in life-threatening adrenal insufficiency soon after birth. The STAR gene has seven exons, is located at chromosome 8p11.23, and encodes a 285–amino acid protein that regulates the flow of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane enzyme, where the biosynthesis of steroid initiates [7]. Glucose regulatory protein 78 (GRP78), a master endoplasmic reticulum chaperone, is necessary for STAR expression and activity by facilitating the intermediate folding of STAR for delivery to the outer mitochondrial membrane. In the absence of GRP78, appropriate folding of STAR is lost, resulting in ablation of STAR expression and complete shutdown of mitochondrial steroidogenesis [8]
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