Identification of a Novel Missense Mutation That Is as Damaging to DAX-1 Repressor Function as a Nonsense Mutation

Brown, Pamela; Scobie, Graeme; Townsend, Julie; Bayne, Rosemary A. L.; Saunders, Philippa T. K.; Anderson, Richard A.

doi:10.1210/jc.2002-021560

Cited by 22 publications

(39 citation statements)

References 66 publications

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“…Testicular biopsy has been performed in a small number of DAX1-mutated men, showing diverse histological aspects (8,17,19,23). The first biopsy reported in an adult male was performed at the age of 27, following 7 years of hCG treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Biopsy revealed disorganization of the normal tubule structure and abnormal proliferation of interstitial tissue, as well as moderate Leydig cell hyperplasia, possibly related to chronic hCG administration. Interestingly, postmortem examination of a neonate who died at 23 days revealed normal testicular histology (23) with the presence of well-defined seminiferous testis cords containing numerous Sertoli cells and germ cells. This is compatible with a progressive deterioration of testicular function due to DAX1 mutations, as observed in our patient.…”

Section: Discussionmentioning

confidence: 99%

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A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

Raffin-Sanson

Oudet

Salenave

et al. 2013

European Journal of Endocrinology

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Objective: DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia. Case report: The proband was referred for infertility at the age of 32 years. He reported adrenal insufficiency diagnosed at the age of 19 years. Puberty started at the age of 13 years, with spontaneous virilization, growth spurt, and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length, and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic-pituitary-gonadal axis with normal testosterone and inhibin B; basal and GNRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew, and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild HHG, and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia. Conclusion: Long-term preservation of normal hypothalamic-pituitary-gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

Raffin-Sanson

Oudet

Salenave

et al. 2013

European Journal of Endocrinology

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“…A testicular biopsy could provide additional information to reveal the mechanism underlying spermatogenic failure in these patients. To date, the only data on testicular histology in DAX1-deficient men have been reported by Brown and colleagues (27) who described normal testicular architecture in an infant who died of AHC. Accordingly, the 'rescue' experiments in DAX1 knockout mice seem to exclude the possibility that abnormalities of the testicular structure are mainly responsible for their infertility.…”

Section: Discussionmentioning

confidence: 99%

DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients

Mantovani

Menis²,

Borretta

et al. 2006

eur j endocrinol

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Objective: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC. Design: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment. Methods: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients' peripheral blood leukocytes and the coding region, splice sites, and promoter (2 240 bp) region of DAX1 were directly sequenced. Results: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelvemonth treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis. Conclusions: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.European Journal of Endocrinology 154 685-689

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“…A neonate who died due to AHC, the sibling of a patient with the c.1197C 1 A variant, predicting p.(Y399 * ), had normal testicular architecture [Brown et al, 2003]. A 9-year-old boy with AHC and undescended, prepubertal testes had the c.1355delT variant; this predicts a frameshift with the first premature termi- nation at codon 461, p.(Ile452Thrfs * 10).…”

Section: Discussionmentioning

confidence: 99%

“…Point mutation of NR0B1 was demonstrated to cause both phenotypes of AHC and HH (OMIM 300200), highlighting its importance in the development and function of the adrenal gland and testis . Expression of missense variants in vitro resulted in translation of non-functional or functionally impaired NR0B1 protein [Brown et al, 2003]. Only 3 regulatory variants have been reported and the molecular consequences of NR0B1 mutation upon testis mRNA levels have not been investigated previously.…”

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confidence: 99%

Genetic Analysis of <b><i>NR0B1</i></b> in Congenital Adrenal Hypoplasia Patients: Identification of a Rare Regulatory Variant Resulting in Congenital Adrenal Hypoplasia and Hypogonadal Hypogonadism without Testicular Carcinoma in situ

Walker¹,

Fowkes²,

Saleh

et al. 2012

Sex Dev

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deletion of a direct repeat, c.857_862delTGGTGC predicting p.(Leu286_Val287del); pedigree 4 (English Caucasian), c.1168+1G 1 A, a regulatory variant within the NR0B1 splice donor site. This last male patient, aged 30 years, presented with evidence of HH but incomplete gonadotrophin deficiency, following an earlier diagnosis of Addison's disease at 3 years. Hormonal therapy induced virilisation. Testicular biopsy was performed. The c.1168+1G 1 A variant abrogated normal splicing of testicular mRNA. Histological examination showed poorly organised testicular architecture and absence of spermatozoa. Morphological analyses and the absence of immunohistochemical staining for OCT3/4 excluded the presence of malignant germ cell cancer and its precursor lesion, CIS. These studies add to the knowledge of the types and ethnic diversity of NR0B1 mutations and their associated phenotypes, and provide insight into the assessment and interpretation of testicular histology in AHC and HH. AbstractThere have been few testicular histology reports of adult patients with congenital adrenal hypoplasia/hypogonadal hypogonadism (AHC/HH), but Leydig cell hyperplasia has been observed, an indicator of the possibility of malignant transformation. We aimed to define the basis of AHC/HH in 4 pedigrees of different ethnic backgrounds. One patient was elected to have testicular biopsy which was examined for evidence of carcinoma in situ (CIS). NR0B1 mutation analysis was performed by sequence analysis. NR0B1 expression was investigated by RT-PCR. Testicular biopsy sections were stained with HE or immunostained for OCT3/4, an established marker of CIS. We identified NR0B1 variants in the 4

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Identification of a Novel Missense Mutation That Is as Damaging to DAX-1 Repressor Function as a Nonsense Mutation

Cited by 22 publications

References 66 publications

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients

Genetic Analysis of <b><i>NR0B1</i></b> in Congenital Adrenal Hypoplasia Patients: Identification of a Rare Regulatory Variant Resulting in Congenital Adrenal Hypoplasia and Hypogonadal Hypogonadism without Testicular Carcinoma in situ

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