Characterization of Two Novel Variants of the Steroidogenic Acute Regulatory Protein Identified in a Girl with Classic Lipoid Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the STAR gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH.

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

Italian Journal of Pediatrics ◽

10.1186/s13052-017-0371-y ◽

2017 ◽

Vol 43 (1) ◽

Cited By ~ 2

Author(s):

Carla Bizzarri ◽

Elisa Pisaneschi ◽

Mafalda Mucciolo ◽

Stefania Pedicelli ◽

Daniela Galeazzi ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Insufficiency ◽

Gene Mutation ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Adrenal Hyperplasia ◽

Steroidogenic Acute Regulatory ◽

Star Gene

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A case report of pedigree of a homozygous mutation of the steroidogenic acute regulatory protein causing lipoid congenital adrenal hyperplasia

Medicine ◽

10.1097/md.0000000000006994 ◽

2017 ◽

Vol 96 (21) ◽

pp. e6994 ◽

Cited By ~ 1

Author(s):

Rong Fu ◽

Lin Lu ◽

Jun Jiang ◽

Min Nie ◽

Xiaojing Wang ◽

...

Keyword(s):

Case Report ◽

Congenital Adrenal Hyperplasia ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Homozygous Mutation ◽

Adrenal Hyperplasia ◽

Steroidogenic Acute Regulatory

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New pathogenic variants and insights into pathogenic mechanisms in GRK1-related Oguchi disease

10.1101/2020.02.20.936880 ◽

2020 ◽

Author(s):

James A. Poulter ◽

Molly S. C. Gravett ◽

Rachel L. Taylor ◽

Kaoru Fujinami ◽

Julie De Zaeytijd ◽

...

Keyword(s):

Protein Function ◽

Kinase Domain ◽

Missense Variants ◽

Pathogenic Variants ◽

Oguchi Disease ◽

Whole Exome ◽

Novel Variants ◽

Variation Database ◽

Biallelic Mutations ◽

The Impact

AbstractPurposeBiallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify pathogenic GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity.MethodsPatients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Pathogenic variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools.ResultsWe identified eleven previously unpublished cases with biallelic pathogenic GRK1 variants, including seven novel variants, and reviewed all GRK1 pathogenic variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. Additionally, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate pathogenic from non-pathogenic variants.ConclusionWe identified new GRK1 pathogenic variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function, giving new insights into the mechanisms of pathogenicity. All pathogenic GRK1 variants described to date have been collated into a Leiden Open Variation Database (http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1).

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A novel mutation of the StAR gene with congenital adrenal hyperplasia and its association with heterochromia iridis: a case report

BMC Endocrine Disorders ◽

10.1186/s12902-019-0448-2 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Vera Splittstösser ◽

Felix Schreiner ◽

Bettina Gohlke ◽

Maik Welzel ◽

Paul-Martin Holterhus ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Novel Mutation ◽

Regulatory Protein ◽

Homozygous Mutation ◽

Elevated Concentration ◽

Adrenal Hyperplasia ◽

Heterochromia Iridis ◽

Phenotypical Feature ◽

Steroidogenic Acute Regulatory ◽

Star Gene

Abstract Background We report a novel mutation within the StAR gene, causing congenital adrenal hyperplasia, with the so far unreported association with heterochromia iridis. Case presentation In a now 15-year-old girl (born at 41 + 6 weeks of gestation) adrenal failure was diagnosed in the neonatal period based on the clinical picture with spontaneous hypoglycaemia, hyponatremia and an extremely elevated concentration of ACTH (3381 pmol/l; ref. level 1,1–10,1 pmol/l), elevated renin (836 ng/l; ref. level 5–308 ng/l), and a decreased concentration of aldosterone (410 pmol/l; ref. level 886–3540 pmol/l). In addition to hyperpigmented skin the patient exhibited sectorial heterochromia iridis. Sequence analysis of the steroidogenic acute regulatory protein (StAR) gene showed a novel homozygous mutation (c.652G > A (p.Ala218Thr), which was predicted in-silico to be possibly damaging. Under daily steroid substitution her electrolyte levels are balanced while she became obese. Puberty occurred spontaneously. Conclusion A novel mutation in the StAR gene was identified in a patient with severe adrenal hypoplasia and sectorial heterochromia iridis. We discuss a causal relationship between these two rare phenotypes, i.e. whether very high levels of ACTH and alpha-MSH during early development might have disturbed early differentiation and distribution of uveal melanocytes. If confirmed in additional cases, discolorization of the iris might be considered as an additional phenotypical feature in the differential diagnosis of congenital adrenal insufficiency.

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Congenital adrenal hyperplasia

Oxford Textbook of Endocrinology and Diabetes ◽

10.1093/med/9780199235292.003.0616 ◽

2011 ◽

pp. 865-878

Author(s):

Nils Krone

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Regulatory Protein ◽

Signs And Symptoms ◽

Adrenal Hyperplasia ◽

Steroidogenic Enzymes ◽

Autosomal Recessive Disorders ◽

Chain Cleavage ◽

Adrenal Steroidogenesis ◽

Steroidogenic Acute Regulatory ◽

Recessive Disorders

Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive disorders of steroidogenesis caused by defects in steroidogenic enzymes involved in glucocorticoid synthesis or in enzymes providing cofactors to steroidogenic enzymes (1, 2). Congenital lipoid adrenal hyperplasia (CLAH) caused by steroidogenic acute regulatory protein (StAR) deficiency is distinct in origin and presentation from the conventional variants of CAH, with the unique feature of lipid accumulation subsequently leading to destruction of adrenal function. This chapter will also mention aldosterone synthase deficiency, which is the only defect in adrenal steroidogenesis causing deficient mineralocorticoid biosynthesis without affecting glucocorticoid biosynthesis. The disorder cannot strictly be considered a CAH variant as it does not result in increased ACTH drive and thus not in adrenal hyperplasia. Novel forms of CAH have emerged during recent years. These include P450 oxidoreductase deficiency (ORD), P450 side-chain cleavage (CYP11A1) deficiency, the nonclassic form of CLAH (StAR deficiency), and apparent cortisone reductase deficiency. All forms of congenital adrenal hyperplasia resemble a disease continuum spanning from mild nonclassic presentations to classic onset with severe signs and symptoms.

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