Identification of Novel Mutations in STAR Gene in Patients with Lipoid Congenital Adrenal Hyperplasia: A First Report from India

Vasudevan, Lakshmi; Joshi, Rajesh; Das, Dhanjit Kumar; Rao, Sudha; Sanghavi, Daksha; Babu, Shiny; Tamhankar, Parag M

doi:10.4274/jcrpe.927

Cited by 8 publications

(6 citation statements)

References 15 publications

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“…FGD is a rare autosomal recessive condition with no racial predilection. Cases of the condition have been reported in white [4] , [12] , black, Indian [5] , and Middle Eastern [13] populations. To our knowledge, our patient is the first reported Chinese Han patient with FGD type 2, with a known MRAP mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Affected individuals typically present with hyperpigmentation, hypoglycemic seizures, failure to thrive, failure to thrive and recurrent infections [1] . Causal mutations of FGD have been identified in MC2R [2] , MRAP [3] , MCM4 [1] , TXNRD2 [4] , STAR [5] and NNT [4] . MC2R accessory protein (MRAP), a 19-kDa single-transmembrane domain protein, is essential for trafficking of MC2R from the endoplasmic reticulum (ER) to the cell surface and subsequent signaling in response to ACTH [6] .…”

Section: Introductionmentioning

confidence: 99%

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Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

Chen

Zhou

Fang

et al. 2016

Molecular Genetics and Metabolism Reports

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Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder in which the adrenal cortex fails to respond appropriately to stimulation by adrenocorticotropic hormone (ACTH) to produce cortisol. The disease is characterized in laboratory testing by glucocorticoid deficiency and markedly elevated ACTH levels. FGD may present in infancy or early childhood with symptoms related to low cortisol and high ACTH, such as hyperpigmentation, severe hypoglycemia, failure to thrive and recurrent infections. Mutations in the MC2R accessory protein (MRAP) cause FGD types 2, which accounts for approximately 15–20% of FGD cases. Here, we report a female neonate of Chinese Han origin, who presented with noted hyperpigmentation at birth. Laboratory investigations revealed hypocortisolaemia (cortisol < 1.0 μg/dl) and elevated plasma ACTH (1051 pg/ml). She responded to hydrocortisone treatment. Genetic studies confirmed the diagnosis showing homozygous deletion (c. 106 + 1delG) in intron 3 of MRAP gene, a mutation already reported as responsible for FDG type 2. This mutation can cause complete lack of ACTH response thus explaining the early presentation in this case. Her parents and maternal grandmother were heterozygous for the same mutation. To our knowledge, this is the first Chinese Han patient reported with FGD type 2 due to a known MRAP mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

Chen

Zhou

Fang

et al. 2016

Molecular Genetics and Metabolism Reports

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“…Some STAR mutations have been repeatedly identified in specific ethnic groups: Gln258Ter in East Asians, p.Tyr68GlufsTer2 in Palestinians, Leu260Pro in the Swiss population and so on 10,11,13–15 . The reports on LCAH India are scarce 16–18 . We describe our centre's experience with LCAH and a systematically review genetically proven LCAH probands to understand the phenotype–genotype correlation.…”

Section: Introductionmentioning

confidence: 99%

“…10,11,[13][14][15] The reports on LCAH India are scarce. [16][17][18] We describe our centre's experience with LCAH and a systematically review genetically proven LCAH probands to understand the phenotype-genotype correlation. We review the testicular histology and gonadal malignancy at various pubertal stages in 46,XY LCAH.…”

Section: Introductionmentioning

confidence: 99%

Steroidogenic acute regulatory protein (STAR) deficiency: Our experience and systematic review for phenotype–genotype correlation

Phadte,

Dhole,

Hegishte

et al. 2024

Clinical Endocrinology

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ObjectiveLipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype–genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype–genotype correlation.Design, Patients and MeasurementsRetrospective review of three genetically proven LCAH patients from our centre and per‐patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia).ResultsWe report three new LCAH probands from India, all diagnosed post‐infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two‐thirds of LCAH probands were East‐Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice‐site variants and deletion/insertions were present in Group A.ConclusionsWe report three new cases of LCAH from India. We propose a phenotype‐derived genotypic classification of reported STAR variants in 46,XY LCAH.

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“…Even though MC2R and MRAP are the 2 most common causes of FGD, due to advances in genome sequencing, recently several other genes which lead to adrenal insufficiency have been identified. These genes include minichromosomal maintenance-4 deficiency ( MCM4 ) [ 5 ], nicotinamide nucleotide transhydrogenase ( NNT ) [ 6 ], steroid acute regulatory ( STAR ) [ 7 ], thioredoxin reductase 2 ( TXNRD2 ) [ 8 ], and sphingosine-1-phosphate lyase ( SGPL1 ) [ 9 ].…”

mentioning

confidence: 99%

A Novel Homozygous MC2R Variant Leading to Type-1 Familial Glucocorticoid Deficiency

Mohammed

Haris

Hussain

2022

Journal of the Endocrine Society

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Context Type 1 familial glucocorticoid deficiency (FGD) (OMIM #607397) is a rare autosomal recessive disorder due to mutations in melanocortin-2-receptor (MC2R) gene encoding the G protein-coupled adrenocorticotropic (ACTH) transmembrane receptor. Objective The aim of the study is to describe 2 siblings born to a healthy consanguineous family presenting with clinical and biochemical features of FGD, harboring a novel homozygous MC2R variant. Methods Both patients are siblings born at term via normal delivery with normal birth weights. The first sibling presented with symptoms of hypoglycemia, repeated episodes of infections starting from 2 days of age. At 18 months of age, low serum cortisol was found, and he was started on hydrocortisone replacement therapy. The second sibling developed hypoglycemia on day 1 after birth, investigations revealed low serum sodium and cortisol levels and was also commenced on hydrocortisone treatment. Whole exome sequencing (WES) and in vitro functional studies on cell line transfected with wild-type and mutant plasmid clones were undertaken. Results WES revealed a novel homozygous missense mutation c.326T>A, p.Leu109Gln in the MC2R gene. In-silico prediction tools predicted the effect of this mutation to be deleterious. In vitro study using HEK293 cells transfected with MC2R wild-type and mutant clones showed a defect in protein expression and cAMP generation when stimulated with ACTH. Conclusion Homozygous semiconserved p.Leu109Gln mutation disrupts cAMP production and MC2R protein expression leading to ACTH resistance. This study provides additional evidence that this novel pathogenic variant in MC2R results in FGD phenotypes.

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Identification of Novel Mutations in STAR Gene in Patients with Lipoid Congenital Adrenal Hyperplasia: A First Report from India

Cited by 8 publications

References 15 publications

Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

Steroidogenic acute regulatory protein (STAR) deficiency: Our experience and systematic review for phenotype–genotype correlation

A Novel Homozygous MC2R Variant Leading to Type-1 Familial Glucocorticoid Deficiency

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