DAX1 Mutations Map to Putative Structural Domains in a Deduced Three-Dimensional Model

Zhang, Yao Hua; Guo, Weiwen; Wagner, Richard; Huang, Bing; McCabe, Linda L.; Vilain, Éric; Burris, Thomas P.; Anyane‐Yeboa, Kwame; Burghes, Arthur H.M.; Chitayat, David; Chudley, Albert E.; Genel, Myron; Gertner, Joseph M.; Klingensmith, Georgeanna J.; Levine, Steven N.; Nakamoto, Jon; New, Maria I.; Pagon, Roberta A; Pappas, John; Quigley, Charmian A.; Rosenthal, Ira M.; Baxter, John D.; Fletterick, Robert J.; McCabe, Edward R.B.

doi:10.1086/301782

Cited by 97 publications

(76 citation statements)

References 46 publications

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“…Previous reports have suggested that the majority of missense mutations are concentrated in the LDB-like region (Phelan and McCabe, 2001;Zhang, et al, 1998). However, this report provides further evidence that there is no existence of mutational hotspots concerning frameshift and nonsense mutations in the NR0B1 gene.…”

Section: Resultscontrasting

confidence: 48%

“…This observation is consistent with the overall distribution of NR0B1 mutations (Phelan and McCabe, 2001) and thus explains that the majority of the novel mutations reported are frameshift mutations. The occurrence of the 734_740del mutation in two unrelated families is a rare phenomenon, while only a few other mutations have been reported to occur in unrelated families (c.501del (Zhang, et al, 2001), c.1292del (Guo, et al, 1995;Zhang, et al, 1998)). The frameshift and nonsense mutations were detected throughout the entire NR0B1 coding region (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Thirteen novel mutations in theNR0B1(DAX1) gene as cause of adrenal hypoplasia congenita

et al. 2005

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X-linked adrenal hypoplasia congenita (AHC) is a rare developmental disorder associated with primary adrenal insufficiency and combined primary and secondary male hypogonadism. It is caused by deletions or mutations of the NR0B1 (DAX1) gene encoding DAX1, an atypical orphan member of the nuclear receptor superfamily. The continuous molecular genetic analysis of male patients with primary adrenal insufficiency revealed 13 novel mutations within the coding region of the NR0B1 gene which are predicted to inactivate the DAX1 function. These were three nonsense mutations (c.312C>A, p.Cys104X, c.670C>T, p.Gln224X; and c.873G>A, p.Trp291X), five duplications (c.269_270dup, c.421_422dup, c.895_896dup, c.989dup, c.999_1000dup), and five deletions (c.483del, c.745_746del, c.734_740del, c.1092del, and c.1346del). All of the mutations resulted in a premature stop codon destroying the ligand binding domain of the predictive DAX1 protein.

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Section: Resultscontrasting

confidence: 48%

Section: Resultsmentioning

confidence: 99%

Thirteen novel mutations in theNR0B1(DAX1) gene as cause of adrenal hypoplasia congenita

et al. 2005

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“…3A; A of the ATG start codon designated ϩ1; 501delA of IV-2 previously reported (22)]. This single nucleotide deletion results in a frame shift and premature stop codon at position 263.…”

Section: Mutation Analysis Of the Dax1 Genementioning

confidence: 87%

X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females

Seminara¹

1999

Journal of Clinical Endocrinology & Metabolism

106

124

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X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary adrenal insufficiency and hypogonadotropic hypogonadism (HH). The gene responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone receptor superfamily. We studied an extended kindred with AHC and HH in which two males (the proband and his nephew) were affected with a nucleotide deletion (501delA). The proband's mother, sister, and niece were heterozygous for this frameshift mutation. At age 27 yr, after 7 yr of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal administered over a 3-yr period, the proband remained azoospermic. The proband's mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17-18 yr.Baseline patterns of pulsatile gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the affected males. LH, FSH, and free ␣-subunit were determined during 12.5-24 h of frequent blood sampling (every 10 min). Both patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6 -7 days. Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess the pituitary responsiveness to exogenous GnRH. In the proband, FSH and LH levels demonstrated a subtle, but significant, response to GnRH over the week of pulsatile GnRH therapy. Free ␣-subunit levels demonstrated an erratic pattern of secretion at baseline and no significant response to pulsatile GnRH.We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred. (J Clin Endocrinol Metab 84: [4501][4502][4503][4504][4505][4506][4507][4508][4509] 1999) A DRENAL hypoplasia congenita is a rare developmental disorder of the adrenal gland. In the X-linked cytomegalic form, the adrenal glands lack the permanent adult zone of the adrenal cortex (1). Affected boys typically present with adrenal insufficiency in early infancy or childhood and hypogonadotropic hypogonadism (HH) at the time of puberty (2). The gene responsible for adrenal hypoplasia congenita (AHC) is DAX1 (dosage-sensitive, sex reversal, adrenal hypoplasia congenita, critical region on the X-chromosome, gene 1), which encodes for a protein that is a member of the orphan nuclear hormone receptor superfamily (3, 4). Although the carboxyl-terminus of DAX-1 (putative ligand-binding domain) displays sequence homology with several other transcription factors, the amino-terminus of DAX-1 has a novel amino acid tandem repeat structure that lacks the zinc finger motif typically...

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“…The gel is stained and a scanned image of the gel is obtained. Two images from a control and a test sample or samples stimulated under two different environmental conditions are obtained and compared for differences in protein expression or protein modification [6,7]. An example is provided in Fig.…”

Section: General Optical Image Technologiesmentioning

confidence: 99%

Proteome imaging: A closer look at life's organization

Heeren

2005

Proteomics

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Imaging the proteome is a term that is used in many different contexts. The term implies that the entire cohort of proteins and their modifications are visualized. This unfortunately is not the case. In this mini-review, a concise overview is provided on different imaging technologies that are currently used to investigate the structure, function and dynamics of proteins and their organization. These techniques have been selected for review based on the unique insights they provide in subsets of the proteome. These techniques have been illustrated with practical examples of their merits. Mass spectrometry-based imaging technologies are playing a key role in proteome research and have been reviewed in more detail. They hold the promise of detailed molecular insight in the spatial organization of living system.

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DAX1 Mutations Map to Putative Structural Domains in a Deduced Three-Dimensional Model

Cited by 97 publications

References 46 publications

Thirteen novel mutations in theNR0B1(DAX1) gene as cause of adrenal hypoplasia congenita

Thirteen novel mutations in theNR0B1(DAX1) gene as cause of adrenal hypoplasia congenita

X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females

Proteome imaging: A closer look at life's organization

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