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Identification of novel mutations in STAR gene in patients with lipoid congenital adrenal hyperplasia: a first report from India.

ABSTRACT: Lipoid congenital adrenal hyperplasia (LCAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. We report novel molecular findings of three unrelated infants with LCAH diagnosed at our center. A known missense mutation c.653C>T (p.A218V) and two novel mutations [premature termination c.441G>A (or p.W147X) and frameshift deletion c.del815G (or p.R272PfsX35)] were identified after complete sequencing of the STAR gene. Prenatal diagnosis was carried out for the family with mutation c.815delG by molecular testing wherein the fetus was found to be homozygous for the mutation. This is the first report of molecular diagnosis and prenatal testing for LCAH from India.

SUBMITTER: Vasudevan L

PROVIDER: S-EPMC3701918 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Identification of novel mutations in STAR gene in patients with lipoid congenital adrenal hyperplasia: a first report from India.

Vasudevan Lakshmi L Joshi Rajesh R Das Dhanjit Kumar DK Rao Sudha S Sanghavi Daksha D Babu Shiny S Tamhankar Parag M PM

Journal of clinical research in pediatric endocrinology 20130101 2

Lipoid congenital adrenal hyperplasia (LCAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. We report novel molecular findings of three unrelated infants with LCAH diagnosed at our center. A known missense mutation c.653C>T (p.A218V) and two novel mutations [premature termination c.441G>A (or p.W147X) and frameshift deletion c.del815G (or p.R272PfsX35)] were identified after complete sequencing of the STAR gene. Prenatal diagnosis was carried out for the family with mu ...[more]

PMID: 23748066

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Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient.

Project description:UnlabelledLipoid congenital adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is most commonly caused by mutations in steroidogenic acute regulatory protein (STAR), which is required for the movement of cholesterol from the outer to the inner mitochondrial membranes to synthesize pregnenolone. This study was performed to evaluate whether the salt-losing crisis and the adrenal inactivity experienced by a Scandinavian infant is due to a de novo STAR mutation. The study was conducted at the University of North Dakota, the Mercer University School of Medicine and the Memorial University Medical Center to identify the cause of this disease. The patient was admitted to a pediatric endocrinologist at the Sanford Health Center for salt-losing crisis and possible adrenal failure. Lipoid CAH is an autosomal recessive disease, we identified two de novo heterozygous mutations (STAR c.444C>A (STAR p.N148K) and STAR c.557C>T (STAR p.R193X)) in the STAR gene, causing lipoid CAH. New onset lipoid CAH can occur through de novo mutations and is not restricted to any specific region of the world. This Scandinavian family was of Norwegian descent and had lipoid CAH due to a mutation in S TAR exons 4 and 5. Overexpression of the STAR p.N148K mutant in nonsteroidogenic COS-1 cells supplemented with an electron transport system showed activity similar to the background level, which was ?10% of that observed with wild-type (WT) STAR. Protein-folding analysis showed that the finger printing of the STAR p.N148K mutant is also different from the WT protein. Inherited STAR mutations may be more prevalent in some geographical areas but not necessarily restricted to those regions.Learning pointsSTAR mutations cause lipoid CAH.This is a pure population from a caucasian family.Mutation ablated STAR activity.The mutation resulted in loosely folded conformation of STAR.

| S-EPMC4815279 | biostudies-literature

Lipoid Congenital Adrenal Hyperplasia With a Novel StAR Gene Mutation.

Project description:Lipoid congenital adrenal hyperplasia (LCAH) is characterized by disturbance of adrenal and gonadal steroidogenesis (OMIM:201710). It is caused by mutation in the Steroidogenic Acute Regulatory Protein (StAR). We report a classic case of LCAH in a neonate (46, XY) with phenotypic female genitalia who presented with significant salt loss with a novel homozygous variant mutation c.745-1G>C p. in StAR gene.

| S-EPMC10226314 | biostudies-literature

Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia.

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Novel STAR gene variant in a patient with classic lipoid congenital adrenal hyperplasia and combined pituitary hormone deficiency.

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| S-EPMC7859387 | biostudies-literature

Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency.

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| S-EPMC2860769 | biostudies-literature

Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency.

Project description:Lipoid congenital adrenal hyperplasia (CAH) (OMIM n. 201710) is the most severe form of congenital adrenal hyperplasia. It is characterized by severe adrenal and gonadal steroidogenesis impairment due to a defect in the conversion of cholesterol to pregnenolone. Affected infants experience salt loss, but glucocorticoid and mineralocorticoid replacement therapy enables long-term survival. Classic lipoid congenital adrenal hyperplasia is relatively common in Japan and Korea but extremely rare in Caucasian populations.A female infant of Italian origin came to our attention in late infancy with a clinical picture of acute adrenal insufficiency. The study of the STAR gene revealed two genomic variants c.562C > T and c.577C > T in compound heterozygosity. At the protein level, the two mutations determine the p.Arg188Cys variant (rs104894090) and the p.Arg193Ter variant (rs387907235), respectively. Sanger sequencing was used to confirm the identified variants and to perform familial study. The mother carried the p.Arg188Cys variant, while the father carried the p.Arg193Ter variant.To our knowledge this is the second case of classic lipoid congenital adrenal hyperplasia reported in the Italian population. STAR mutations resulting in lipoid congenital adrenal hyperplasia should be considered all over the world in the differential diagnosis of newborn babies and infants with primary adrenal insufficiency.

| S-EPMC5480121 | biostudies-literature

Long-term follow-up in a Chinese child with congenital lipoid adrenal hyperplasia due to a StAR gene mutation.

Project description:BACKGROUND:Congenital lipoid adrenal hyperplasia (CLAH) is an extremely rare and the most severe form of congenital adrenal hyperplasia. Typical features include disorder of sex development, early-onset adrenal crisis and enlarged adrenal glands with fatty accumulation. CASE PRESENTATION:We report a case of CLAH caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. The patient had typical early-onset adrenal crisis at 2 months of age. She had normal-appearing female genitalia and a karyotype of 46, XY. The serum cortisol and adrenal steroids levels were always nearly undetectable, but the adrenocorticotropic hormone levels were extremely high. Genetic analysis revealed compound heterozygous mutations at c. 229C?>?T (p.Q77X) in exon 3 and c. 722C?>?T (p.Q258X) in exon 7 of the StAR gene. The former mutation was previously detected in only two other Chinese CLAH patients. Both mutations cause truncation of the StAR protein. The case reported here appears to be a classic example of CLAH with very small adrenal glands and is the second reported CLAH case with small adrenal glands thus far. In a 15-year follow-up, the patient's height was approximately average for females before age 4 and fell to -?1 SDS at 10 years of age. Her bone age was similar to her chronological age from age 4 to age 15 years. CONCLUSIONS:In conclusion, this is a classic case of CLAH with exceptionally small adrenal glands. Q77X mutation seems to be more common in Chinese CLAH patients. Additionally, this is the first report of the growth pattern associated with CLAH after a 15-year follow-up.

| S-EPMC6219181 | biostudies-literature

Mutation Spectrum of STAR and a Founder Effect of the p.Q258* in Korean Patients with Congenital Lipoid Adrenal Hyperplasia.

Project description: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 a 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 (STR) 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 corresponded with the date 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.

| S-EPMC5522967 | biostudies-literature

Clinical and functional analyses of the novel STAR c.558C>A in a patient with classic lipoid congenital adrenal hyperplasia.

Project description:Objective: Congenital lipid adrenal hyperplasia (LCAH) is the most serious type of congenital adrenal hyperplasia and is caused by steroid-based acute regulatory (STAR) protein mutations. Herein, we report compound heterozygous mutations c.558C>A (p.S186 R) and c.772C>T (p.Q258*) in a newborn 46 XY patient diagnosed with classic LCAH and explore their clinical and functional characteristics. Methods: Peripheral blood samples were collected from LCAH patient and their families. The pathogenic variant identified by whole-exome sequencing was further confirmed by Sanger sequencing and pedigree verification. The functional consequence and ability to convert cholesterol into progesterone of the identified STAR Q258* and S186 R mutations were analyzed by cell transfection and in vitro assays. Results: The proband was presented with severe glucocorticoid and mineralocorticoid deficiency, high adrenocorticotropic hormone, and enlarged adrenals. Heterozygous mutations p. S186 R and p. Q258* in the STAR gene were identified in the patient, and her parents were carriers, which is consistent with an autosomal recessive disorder. The STAR p. Q258* mutation has been reported and generates a truncated protein. The p. S186 R mutation is a novel variant that disrupts STAR. The residual STAR activities of p. S186R, p. Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, respectively, of the wild-type, proving the main negative effects of the mutant proteins. Conclusion: Our findings reveal the molecular mechanisms underlying LCAH pathogenesis, further expanding the genotype and clinical spectrum of LCAH.

| S-EPMC9887130 | biostudies-literature

A Novel Intronic Pathogenic Variant in <i>STAR</i> With a Dominant Negative Mechanism Causes Attenuated Lipoid Congenital Adrenal Hyperplasia.

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| S-EPMC8114284 | biostudies-literature

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