Novel mutations and spectrum of the disease of NR0B1 (DAX1)-related adrenal insufficiency in Indian children
-
Suchit Gupta
,
Kriti Joshi
Abstract
Background
X-linked adrenal hypoplasia congenita (AHC), due to mutations in the nuclear receptor superfamily 0, group B, member 1 (NR0B1)/dosage-sensitive sex reversal, AHC, critical region on the X chromosome, gene 1 (DAX1) gene, usually presents with a salt-wasting adrenal crisis in infancy and hypogonadotropic hypogonadism (HH) in adolescents. Genetic reports in the literature from patients of diverse ethnicity are limited. We describe the atypical clinical characteristics and molecular genetic results in six Indian patients.
Methods
Both exons and flanking intronic sequences of the NR0B1 gene were amplified and sequenced in five patients. In the sixth patient, suspected to have a large deletion, multiplex ligation-dependent probe amplification (MLPA) and chromosomal microarray analysis were performed.
Results
Sequencing revealed three novel mutations: a nonsense mutation (c.776C > A), a deletion (c.298del), both causing loss of domains which are highly conserved among nuclear receptor families, and a missense mutation (c.1112T > C). In-silico analysis by structure-based protein modeling predicted a de-stabilizing effect of the novel missense mutation. Two previously reported mutations were seen in patients with atypical manifestations such as late-onset adrenal insufficiency and precocious puberty. One patient had a 7.15-Mb contiguous deletion involving the NR0B1, Duchenne muscular dystrophy (DMD), glycerol kinase (GK) and melanoma antigen, family B, 16 (MAGEB16) genes.
Conclusions
Our report emphasizes the wide clinical spectrum of AHC, including rare manifestations, and enumerates unique mutations in the NR0B1 gene.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved the submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, et al.An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 1994;372:635–41.10.1038/372635a0Suche in Google Scholar PubMed
2. Guo W, Burris TP, Zhang YH, Huang BL, Mason J, et al. Genomic sequence of the DAX1 gene: an orphan nuclear receptor responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1996;81:2481–6.10.1210/jc.81.7.2481Suche in Google Scholar
3. Muscatelli F, Strom TM, Walker AP, Zanaria E, Recan D, et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 1994;372:672–6.10.1038/372672a0Suche in Google Scholar PubMed
4. Peter M, Viemann M, Partsch CJ, Sippell WG. Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene. J Clin Endocrinol Metab 1998;83:2666–74.10.1210/jcem.83.8.5027Suche in Google Scholar PubMed
5. Suzuki T, Kasahara M, Yoshioka H, Morohashi K, Umesono K. LXXLL-related motifs in Dax-1 have target specificity for the orphan nuclear receptors Ad4BP/SF-1 and LRH-1. Mol Cell Biol 2003;23:238–49.10.1128/MCB.23.1.238-249.2003Suche in Google Scholar PubMed PubMed Central
6. Ito M, Yu R, Jameson JL. DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol 1997;17:1476–83.10.1128/MCB.17.3.1476Suche in Google Scholar PubMed PubMed Central
7. Lin L, Gu WX, Ozisik G, To WS, Owen CJ, et al. Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years’ experience. J Clin Endocrinol Metab 2006;91:3048–54.10.1210/jc.2006-0603Suche in Google Scholar PubMed PubMed Central
8. Tabarin A, Achermann JC, Recan D, Bex V, Bertagna X, et al.A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism. J Clin Invest 2000;105:321–8.10.1172/JCI7212Suche in Google Scholar PubMed PubMed Central
9. Ozisik G, Mantovani G, Achermann JC, Persani L, Spada A, et al.An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 2003;88:417–23.10.1210/jc.2002-021034Suche in Google Scholar PubMed
10. Raffin-Sanson ML, Oudet B, Salenave S, Brailly-Tabard S, Pehuet M, et al. A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up. Eur J Endocrinol 2013;168:K45–50.10.1530/EJE-12-1055Suche in Google Scholar PubMed
11. Mantovani G, Ozisik G, Achermann JC, Romoli R, Borretta G, et al.Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 2002;87:44–8.10.1210/jcem.87.1.8163Suche in Google Scholar PubMed
12. Oh CM, Chun S, Lee JE, Lee JS, Park S, et al.A novel missense mutation in NR0B1 causes delayed-onset primary adrenal insufficiency in adults. Clin Genet 2017;92:344–6.10.1111/cge.12966Suche in Google Scholar PubMed
13. Domenice S, Latronico AC, Brito VN, Arnhold IJ, Kok F, et al.Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene. J Clin Endocrinol Metab 2001;86:4068–71.10.1210/jcem.86.9.7816Suche in Google Scholar PubMed
14. Verrijn Stuart AA, Ozisik G, de Vroede MA, Giltay JC, Sinke RJ, et al. An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency. J Clin Endocrinol Metab 2007;92:755–61.10.1210/jc.2005-2429Suche in Google Scholar PubMed
15. Loke KY, Larry KS, Lee YS, Peter M, Drop SL. Prepubertal diagnosis of X-linked congenital adrenal hypoplasia presenting after infancy. Eur J Pediatr 2000;159:671–5.10.1007/PL00008404Suche in Google Scholar
16. Liu Y, Yuan J, Zhang H, Jiang Y, Qin G. A novel DAX-1 mutation in two male siblings presenting with precocious puberty and late-onset hypogonadotropic hypogonadism. J Pediatr Endocrinol Metab 2017;30:349–53.10.1515/jpem-2016-0228Suche in Google Scholar PubMed
17. Rojek A, Krawczynski MR, Jamsheer A, Sowinska-Seidler A, Iwaniszewska B, et al. X-linked adrenal hypoplasia congenita in a boy due to a novel deletion of the entire NR0B1 (DAX1) and MAGEB1-4 genes. Int J Endocrinol 2016;2016:e5178953.10.1155/2016/5178953Suche in Google Scholar PubMed PubMed Central
18. Okutman O, Muller J, Skory V, Garnier JM, Gaucherot A, et al.A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family. J Assist Reprod Genet 2017;34:683–94.10.1007/s10815-017-0900-zSuche in Google Scholar PubMed PubMed Central
19. Achermann JC, Gu WX, Kotlar TJ, Meeks JJ, Sabacan LP, et al.Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay. J Clin Endocrinol Metab 1999;84:4497–500.10.1210/jc.84.12.4497Suche in Google Scholar
20. Richards S, Aziz N, Bale S, Bick D, Das S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24.10.1038/gim.2015.30Suche in Google Scholar PubMed PubMed Central
21. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, et al. The Ensembl Variant Effect Predictor. Genome Biol 2016;17:122.10.1186/s13059-016-0974-4Suche in Google Scholar PubMed PubMed Central
22. Wang C, Zhang H, Zheng WM, Xu D, Zhu J, et al. FALCON@home: a high-throughput protein structure prediction server based on remote homologue recognition. Bioinformatics 2016;32:462–4.10.1093/bioinformatics/btv581Suche in Google Scholar
23. Heo L, Park H, Seok C. Galaxy Refine: protein structure refinement driven by side-chain repacking. Nucleic Acids Res 2013;41:W384–8.10.1093/nar/gkt458Suche in Google Scholar
24. Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 2005;33:W306–10.10.1093/nar/gki375Suche in Google Scholar
25. Pires DE, Ascher DB, Blundell TL. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res 2014;42:W314–9.10.1093/nar/gku411Suche in Google Scholar
26. Meloni A, Meloni A, Cao A, Rosatelli MC. New frameshift mutation in the DAX-1 gene in a patient with X-linked adrenal hypoplasia and hypogonadotropic hypogonadism. Hum Mutat 1996;8:183–4.10.1002/(SICI)1098-1004(1996)8:2<183::AID-HUMU12>3.0.CO;2-ZSuche in Google Scholar
27. Krone N, Riepe FG, Dorr HG, Morlot M, Rudorff KH, et al. Thirteen novel mutations in the NR0B1 (DAX1) gene as cause of adrenal hypoplasia congenita. Hum Mutat 2005;25:502–3.10.1002/humu.9331Suche in Google Scholar
28. Khadilkar VV, Mangtani HR, Jahagirdar RR, Khatod KA, PhadkeND, et al. Entire DAX1 gene deletion in an Indian boy with adrenal hypoplasia congenita. Indian J Pediatr 2012;80:631–5.10.1007/s12098-012-0946-ySuche in Google Scholar
29. Reutens AT, Achermann JC, Ito M, Ito M, Gu WX, et al. Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita. J Clin Endocrinol Metab 1999;84:504–11.10.1210/jc.84.2.504Suche in Google Scholar
30. Nakae J, Tajima T, Kusuda S, Kohda N, Okabe T, et al. Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 1996;81:3680–5.10.1210/jcem.81.10.8855822Suche in Google Scholar
31. Rodríguez Estévez A, Pérez-Nanclares G, Fernández-Toral J, Rivas-Crespo F, López-Siguero JP, et al. Clinical and molecular characterization of five Spanish kindreds with X-linked adrenal hypoplasia congenita: atypical findings and a novel mutation in NR0B1. J Pediatr Endocrinol Metab 2015;28:1129–37.10.1515/jpem-2014-0472Suche in Google Scholar
32. Jadhav U, Harris RM, Jameson JL. Hypogonadotropic hypogonadism in subjects with DAX1 mutations. Mol Cell Endocrinol 2011;346:65–73.10.1016/j.mce.2011.04.017Suche in Google Scholar
33. Rojek A, Obara-Moszynska M, Malecka E, Slomko-Jozwiak M, Niedziela M. NR0B1 (DAX1) mutations in patients affected by congenital adrenal hypoplasia with growth hormone deficiency as a new finding. J Appl Genet 2013;54:225–30.10.1007/s13353-013-0135-3Suche in Google Scholar
34. Argente J, Ozisik G, Pozo J, Munoz MT, Soriano-Guillen L, et al.A novel single base deletion at codon 434 (1301delT) of the DAX1 gene associated with prepubertal testis enlargement. Mol Genet Metab 2003;78:79–81.10.1016/S1096-7192(02)00198-1Suche in Google Scholar
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2018-0440).
©2019 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Mini Review
- Endocrine manifestations of PHACE syndrome
- Original Articles
- Quantitation of the arginine family amino acids in the blood of full-term infants perinatally in relation to their birth weight
- Effect of supplementation with omega-3 fatty acids on hypertriglyceridemia in pediatric patients with obesity
- Pediatric diabetes inpatient care: can medical staff knowledge be improved?
- Association of lipid profile and BMI Z-score in southern Iranian children and adolescents
- Arterial stiffness in children and adolescents with and without continuous insulin infusion
- Fasting during the holy month of Ramadan among older children and adolescents with type 1 diabetes in Kuwait
- Evaluation of the relationship between short-term glycemic control and netrin-1, a urinary proximal tubular injury marker in children with type 1 diabetes
- Incidence of diabetic ketoacidosis in newly diagnosed type 1 diabetes children in western Saudi Arabia: 11-year experience
- Novel mutations and spectrum of the disease of NR0B1 (DAX1)-related adrenal insufficiency in Indian children
- Metabolic profile, cardiovascular risk factors and health-related quality of life in children, adolescents and young adults with congenital adrenal hyperplasia
- Safety and effectiveness of growth hormone therapy in infants with Prader-Willi syndrome younger than 2 years: a prospective study
- Response to sapropterin hydrochloride (Kuvan®) in children with phenylketonuria (PKU): a clinical trial
- Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A in children: a single centre experience
- Benign thyroid nodules in pediatric patients: determining best practices for repeat ultrasound evaluations
- Letter to the Editor
- Thyroid function in males with fragile X syndrome
- Case Reports
- A case of a severe reaction following the use of bisphosphonates in a patient with osteogenesis imperfecta
- Cushing disease in a patient with nonbullous congenital ichthyosiform erythroderma: lessons in avoiding glucocorticoids in ichthyosis
- Contiguous gene deletion in a Chinese family with X-linked nephrogenic diabetes insipidus: challenges in early diagnosis and implications for affected families
Artikel in diesem Heft
- Frontmatter
- Mini Review
- Endocrine manifestations of PHACE syndrome
- Original Articles
- Quantitation of the arginine family amino acids in the blood of full-term infants perinatally in relation to their birth weight
- Effect of supplementation with omega-3 fatty acids on hypertriglyceridemia in pediatric patients with obesity
- Pediatric diabetes inpatient care: can medical staff knowledge be improved?
- Association of lipid profile and BMI Z-score in southern Iranian children and adolescents
- Arterial stiffness in children and adolescents with and without continuous insulin infusion
- Fasting during the holy month of Ramadan among older children and adolescents with type 1 diabetes in Kuwait
- Evaluation of the relationship between short-term glycemic control and netrin-1, a urinary proximal tubular injury marker in children with type 1 diabetes
- Incidence of diabetic ketoacidosis in newly diagnosed type 1 diabetes children in western Saudi Arabia: 11-year experience
- Novel mutations and spectrum of the disease of NR0B1 (DAX1)-related adrenal insufficiency in Indian children
- Metabolic profile, cardiovascular risk factors and health-related quality of life in children, adolescents and young adults with congenital adrenal hyperplasia
- Safety and effectiveness of growth hormone therapy in infants with Prader-Willi syndrome younger than 2 years: a prospective study
- Response to sapropterin hydrochloride (Kuvan®) in children with phenylketonuria (PKU): a clinical trial
- Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A in children: a single centre experience
- Benign thyroid nodules in pediatric patients: determining best practices for repeat ultrasound evaluations
- Letter to the Editor
- Thyroid function in males with fragile X syndrome
- Case Reports
- A case of a severe reaction following the use of bisphosphonates in a patient with osteogenesis imperfecta
- Cushing disease in a patient with nonbullous congenital ichthyosiform erythroderma: lessons in avoiding glucocorticoids in ichthyosis
- Contiguous gene deletion in a Chinese family with X-linked nephrogenic diabetes insipidus: challenges in early diagnosis and implications for affected families
