New mutations of DAX-1 genes in two Japanese patients with X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism

Abstract

Congenital adrenal hypoplasia, an X-linked disorder, is characterized by primary adrenal insufficiency and frequent association with hypogonadotropic hypogonadism. The X-chromosome gene DAX-1 has been most recently identified and shown to be responsible for this disorder. We analyzed the DAX-1 genes of two unrelated Japanese patients with congenital adrenal hypoplasia and hypogonadotropic hypogonadism by using PCR amplification of genomic DNA and its complete exonic sequencing. In a family containing several affected individuals, the proband male patient had a stop codon (TGA) in place of tryptophan (TGG) at amino acid position 171. As expected, his mother was a heterozygous carrier for the mutation, whereas his father and unaffected brother did not carry this mutation. In another male patient with noncontributory family history, sequencing revealed a 1-bp (T) deletion at amino acid position 280, leading to a frame shift and, subsequently a premature stop codon at amino acid position 371. The presence of this mutation in the patients' genome was further confirmed by digestion of genomic PCR product with MspI created by this mutation. Family studies using MspI digestion of genomic PCR products revealed that neither parent of this individual carried the mutation. These results clearly indicate that congenital adrenal hypoplasia and hypogonadotropic hypogonadism result from not only inherited but also de novo mutation in the DAX-1 gene.

Hypogonadotropic hypogonadism in subjects with DAX1 mutations

“…1) (Reutens et al, 1999, Lin et al, 2006, Achermann et al, 2000, Muscatelli et al, 1994, Zanaria et al, 1994, Guo, Mason, Stone et al, 1995, Takahashi, Shoji, Haraguchi et al, 1997, Meloni, Cao and Rosatelli, 1996, Nakae, Abe, Tajima et al, 1997, Schwartz, Blichfeldt and Muller, 1997, Peter, Viemann, Partsch et al, 1998, Seminara, Achermann, Genel et al, 1999, Bassett, O’Halloran, Williams et al, 1999, Caron, Imbeaud, Bennet et al, 1999, Merke, Tajima, Baron et al, 1999, Tabarin, Achermann, Recan et al, 2000, Domenice, Latronico, Brito et al, 2001, Wiltshire, Couper, Rodda et al, 2001, Sekiguchi, Hara, Matsuoka et al, 2007, Bernard, Ludbrook, Queipo et al, 2006, Verrijn Stuart, Ozisik, de Vroede et al, 2007, Landau, Hanukoglu, Sack et al, 2010, Li, Liu, Zhang et al, 2010, Sykiotis, Hoang, Avbelj et al, 2010, Abe, Nakae, Yasoshima et al, 1999, Achermann, Meeks and Jameson, 2001, Ahmad, Paterson, Lin et al, 2007, Argente, Ozisik, Pozo et al, 2003, Balsamo, Antelli, Baldazzi et al, 2005, Brown, Scobie, Townsend et al, 2003, Calliari, Longui, Rocha et al, 2007, Frapsauce, Ravel, Legendre et al, 2011, Garcia-Malpartida, Gomez-Balaguer, Sola-Izquierdo et al, 2009, Guo, Burris, Zhang et al, 1996, Habiby, Boepple, Nachtigall et al, 1996, Hamaguchi, Arikawa, Yasunaga et al, 1998, Kinoshita, Yoshimoto, Motomura et al, 1997, Krone, Riepe, Dorr et al, 2005, Lam, Cheng, Poon et al, 2006, Mantovani, Ozisik, Achermann et al, 2002, Mericq, Ciaccio, Marino et al, 2007, Nakae, Tajima, Kusuda et al, 1996, Ozisik, Mantovani, Achermann et al, 2003, Salvi, Gomez, Fiaux et al, 2002, Tsai and Tung, 2005, Wang, Killinger and Hegele, 1999, Wu, Zhang, Zhou et al, 2011, Yanase, Takayanagi, Oba et al, 1996, Zhang, Guo, Wagner et al, 1998, Zhang, Huang, Anyane-Yeboa et al, 2001, Franzese, Brunetti-Pierri, Spagnuolo et al, 2005, Laissue, Copelli, Bergada et al, 2006, Okuhara, Abe, Kondo et al, 2008). After other known causes (i.e., congenital adrenal hyperplasia, CAH) have been excluded, it is estimated that as many as 50% of boys with idiopathic primary adrenal insufficiency may have mutations in DAX1 (…”

Dax-1 as One of the Target Genes of Ad4BP/SF-1

“…By screening of a mouse 129J genomic library (Stratagene, La Jolla, CA) with a 32 P-labeled human DAX-1 gene fragment (68), three positive clones were obtained. The regions containing 5Ј-upstream and two exons were mapped and sequenced.…”

Importance of Genetic Diagnosis of DAX-1 Deficiency: Example from a Large, Multigenerational Family

“…The proband developed adrenal insufficiency only 2.5 years after birth, whereas his distant cousin, although carrying the exact same deletion of DAX-1, experienced an adrenal crisis at the age of 10 days. Such heterogeneity in the phenotypic expression of a given mutation of DAX-1 has already been described in several kindreds [7, 10, 28,31,32,33,34]. It is probably one of the reasons why all the attempts at drawing genotype-phenotype correlations in DAX-1 insufficiency have remained largely elusive.…”