ClinGen Dosage Sensitivity Curation Page

NR0B1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
16684822 Lin et al. (2006) described a total of 37 DAX1/NR0B1 mutations and deletions found from a total of 117 individuals with primary adrenal hypoplasia referred over a ten-year period, including 7 nonsense mutations, 12 frameshift mutations, 8 missense mutations, and 8 deletions including only the NR0B1 gene. All of these changes were identified in 46,XY phenotypic males who had presented with primary adrenal failure in infancy or childhood.
15841486 Krone et al., (2005) described 13 novel variants in NR0B1, including 3 nonsense mutations, 5 intragenic duplications, and 5 intragenic deletions identified in 14 male patients with AHC (X-linked adrenal hypoplasia congenita) in infancy or childhood (prepubertal age) in a total cohort of 35 unrelated patients. All of the variants resulted in a premature stop codon destroying the ligand binding domain of the predictive DAX1/NR0B1 protein. No detailed family history was recorded.
11748852 Zhang YH et al. (2001) describe 11 NR0B1 mutations in patients with AHC including six frameshift, two nonsense and two missense mutations from patients diagnosed with clinical features of AHC. No family history were recorded.

Haploinsufficiency phenotype comments:

Loss of function variants including missense, nonsense, frameshift intragenic deletions and duplications have been reported in individuals with both familial and sporadic adrenal hypoplasia congenita (AHC). These variants cause nonfunctional protein leading to adrenal insufficiency and hypogonadotropic hypogonadism (HH), with a spectrum of clinical manifestation in X-linked AHC. Affected boys typically present with adrenal insufficiency in early infancy or childhood and HH at the time of puberty. Expression of X-linked conditions can sometimes occur in females due to skewed X-inactivation, although X-linked AHC predominantly affects boys. The haploinsufficiency is 3. Partial- or whole-gene deletions of NR0B1 as well as mutations resulting in a loss of function cause X-linked adrenal hypoplasia congenital (AHC) with hypogonadotropic hypogonadism (HH) [MIM 300200]. See also GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1431/ Additional evidence includes: PMID: 20573681 Lin et al. (2010) reported 7 novel DAX1 LoF mutations, 1 nonsense, 4 frameshift and 2 missense mutations from 9 patients with AHC (adrenal hypoplasia congenita) and HHG (Hypogonadotropic hypogonadism). The functional studies showed that nuclear localization, trans-repression of StAR (steroidogenic acute regulatory protein) and LH transcriptional activities, and GnRH expression are impaired by theses DAX1/NOR0B1 mutants. No family history was recorded. PMID: 10599709 Stephanie et al. (1999) report a frameshift mutation (501delA) carried by two males (proband and his nephew). This variant was also identified in the proband?s mother, sister, and niece. He presented clinical manifestation at 11 day of life. Delayed puberty the only manifestation of X-linked DAX1/NOR0B1 gene defects in the female heterozygotes in this family. Restriction enzyme analysis confirmed the hemizygous status of affected males and the heterozygous carrier status of females. No familial X-inactivation study was performed.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

To date, there have been no focal duplications of NR0B1, therefore, the gene has a triplosensitivity score 0. However, duplications of a larger region including this gene have been observed in individuals with 46,XY sex reversal 2 (SRXY2) [MIM 300018]. Please see the related region curation for the "Xp21.2 region (includes NR0B1)" (ISCA-46302) for a full description of the evidence supporting triplosensitivity of this region. While all currently reported duplications include nearby genes, functional data suggest focal NR0B1 duplication in XY individuals would also result in an SRXY2 phenotype. See GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1547/ and PMID 22518125 for a recent review of the literature.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.