Endocrine Abstracts (2004) 8 P15

Adrenal hypoplasia congenita and hypogonadotropic hypogonadism due to a novel splice site mutation in NR0B1

F Saleh1, S-H Kim1, AP Walker2 & PM Bouloux1

1Center for Endocrinology,Department of Medicine,Royal Free and University College Medical School,London,UK; 2Centre for Hepatology,Department of Medicine,Royal Free and University College Medical School,London,UK.

The NR0B1 (Nuclear Receptor Subfamily 0, group b, member 1) gene, originally called DAX1, encodes an atypical member of the nuclear receptor family. It is proposed to co-regulate other nuclear receptors, repress transcription of downstream gene targets such as steroidogenic factor 1 and play a role in testis development and spermatogenesis. The gene has two exons of 1,168 and 345bp, separated by a 3,385bp intron. It is expressed in the hypothalamic-pitutary-adrenal/gonadal axis, including ovaries and testes, and in embryonic stem cells. Several mutations have been reported in patients with X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HH). The aim of this study was to investigate NR0B1 as a candidate gene for a case of AHC and HH. Our patient presented shortly after birth with Addisonian crisis. He subsequently failed to enter puberty spontaneously, and HH was diagnosed. On presentation, aged 32 years, he had significant osteoporosis and low LH (0.5 IU/l), FSH (4 IU/l) and testosterone (0.8nmol/l). Testes volumes were right 2ml and left 3ml. Treatment with HCG (2,000u twice weekly) for four years led to increased testicular volumes (6 and 8ml) and testosterone levels (17nmol/l).

The entire coding sequence and splice sites of NR0B1 were PCR amplified from genomic DNA for direct sequence analysis on both strands. A point mutation was identified at the +1 position of the intron splice donor site (IVS1+1G/A). Since this nucleotide is completely conserved in functional splice donor sites, mutation is predicted to affect mRNA splicing. NR0B1 transcripts will be investigated to determine whether IVS1+1G/A results in a null allele (lack of splicing) or alternatively spliced transcripts (cryptic splice sites). This novel finding confirms the molecular basis of AHC with HH for this patient. This first reported NR0B1 splice mutation is predicted to affect the important cellular process of mRNA splicing.

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