A novel stop-loss DAX1 variant affecting its protein-interaction with SF1 precedes the adrenal hypoplasia congenital with rare spontaneous precocious puberty and elevated hypothalamic-pituitary-gonadal/adrenal axis responses

Yang, Haihua; Wei, Haiyan; Shen, Linghua; C, Selvaa Kumar; Chen, Qiong; Chen, Yongxing; Kumar, Sumit

doi:10.1016/j.ejmg.2021.104192

Cited by 5 publications

(7 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, reduced BTV and low or low-normal inhibin B values for age suggest spermatogenesis failure which can be integrated in the hypogonadotropic hypogonadism profile and in the primary gonadal defect reported in X-AHC patients ( 5 , 9 , 10 , 13 ). As observed here, some authors reported testicular volume ranging from 3 to 6 ml bilaterally in most X-AHC cases ( 6 , 9 , 11 , 25 , 26 , 31 , 32 ). However, testicular volume may be normal in mild forms of X-AHC ( 10 ).…”

Section: Discussionsupporting

confidence: 82%

“…This highlighted the potential deleterious effect of p.(Leu299Pro) for DAX1 protein function. The variant NM_000475.5: c.1411T>C p.(*471Glnext*18) was reported in an X-AHC boy with precocious puberty ( 25 ). Protein–protein docking showed the addition of 18 additional AA after the stop codon decreased interaction between DAX1 protein and SF1 protein.…”

Section: Discussionmentioning

confidence: 99%

“…The boy was followed up from 11 to 15.1 years of age; we do not know whether he would develop hypogonadotropic hypogonadism later. No semen collection was performed, but testicular volume was 3 ml bilaterally and inhibin B levels were low, suggesting a spermatogenesis defect ( 25 ). In contrast, the patient carrying NM_000475.5: c.1411T>C p.(*471Glnext*18) (patient 3) did not present precocious puberty and had subnormal BTV of 20 ml and normal inhibin B level at 15 years and 8 months.…”

Section: Discussionmentioning

confidence: 99%

“…However, testicular volume may be normal in mild forms of X-AHC ( 10 ). Likewise, inhibin B was reported to be low or in the lowest range of normal at puberty or after ( 6 , 10 , 25 , 26 , 31 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants

et al. 2022

View full text Add to dashboard Cite

BackgroundNR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging.ObjectiveThe aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation.PatientsWe included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed.ResultsBilateral testicular volume increased from 8 ml (interquartile range, 6–9) to 12 ml (10–16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46–139) before and 91 ng/L (20–120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any.ConclusionWe characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Yank and colleagues hypothesize weak interactions between DAX-1 and SF1 lead to prolonged activation of hypothalamic NO synthetase and the development of CPP. It is unclear if the findings of Yang et al can be generalized to various pathogenic variants of the NRBOB1 gene (57).…”

Section: Nrob1mentioning

confidence: 99%

A review of the genetics and epigenetics of central precocious puberty

Moise-Silverman

Silverman

2022

Front. Endocrinol.

View full text Add to dashboard Cite

Gonadotrophin dependent sexual precocity, commonly referred to as central precocious puberty (CPP), results from a premature reactivation of the hypothalamic-pituitary-gonadal (HPG) axis before the normal age of pubertal onset. CPP is historically described as girls who enter puberty before the age of eight, and boys before the age of nine. Females are more likely to be diagnosed with idiopathic CPP; males diagnosed with CPP have a greater likelihood of a defined etiology. These etiologies may include underlying CNS congenital defects, tumors, trauma, or infections as well as environmental, genetic, and epigenetic factors. Recently, genetic variants and mutations which may cause CPP have been identified at both the level of the hypothalamus and the pituitary. Single nucleotide polymorphisms (SNPs), monogenetic mutations, and modifications of the epigenome have been evaluated in relationship to the onset of puberty; these variants are thought to affect the development, structure and function of GnRH neurons which may lead to either precocious, delayed, or absent pubertal reactivation. This review will describe recent advances in the field of the genetic basis of puberty and provide a clinically relevant approach to better understand these varying etiologies of CPP.

show abstract

New insights into X‐linked adrenal hypoplasia congenita from a novel splice‐site variant of NR0B1 and adrenal CT images

Jiang

Peng

Zhao

et al. 2023

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background X‐linked adrenal hypoplasia congenita (AHC) is a rare disorder, often manifesting as primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), and caused by variants of NR0B1, most of which are frame‐shifting variants, and few splice‐site variants. Methods and Results Here, a novel splice‐site variant of NR0B1 (NM_000475.4), c.1169‐2A>T (patient 1), and a stop‐loss variant of NR0B1 c.1411T>C (patient 2) are described in this study. We perform minigene assays for the splice‐site variant (c.1169‐2A>T) and determine that the variant causes exon 2 skipping. Moreover, the defect of NR0B1 protein may bring about the severe phenotype of the patient. Through 8 years of follow‐up, we compare the CT images from 8 years ago with the latest image, and observe the CT image change of adrenal in patient 2 (from the increased thickness of adrenal to adrenal atrophy). Conclusion X‐linked adrenal hypoplasia congenita is produced by variants of NR0B1. We report a case that presents a novel splice‐site variant, which has been verified that it could lead to the exon 2 skipping in the RNA splicing progress. Moreover, we report the adrenal CT image change of patient 2, which has never been referred to before, and expand the spectrum of X‐linked AHC characteristics.

show abstract

A novel stop-loss DAX1 variant affecting its protein-interaction with SF1 precedes the adrenal hypoplasia congenital with rare spontaneous precocious puberty and elevated hypothalamic-pituitary-gonadal/adrenal axis responses

Cited by 5 publications

References 61 publications

Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants

Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants

A review of the genetics and epigenetics of central precocious puberty

New insights into X‐linked adrenal hypoplasia congenita from a novel splice‐site variant of NR0B1 and adrenal CT images

Contact Info

Product

Resources

About