Novel mutation of the DAX1 gene in a patient with X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.
X-linked adrenal hypoplasia congenita (AHC) is characterized by primary adrenal insufficiency and is frequently associated with hypogonadotropic hypogonadism (HHG). Mutations of the DAX1 gene have been reported in patients with AHC and HHG. We found a novel DAX1 mutation in our patient. Sequence analysis of the patient's DAX1 demonstrated a 1-bp (G) deletion at codon 49 in exon 1. The mutation shifts the reading frame, resulting in completely different amino acid sequences from codon 49 to the premature stop codon at 84. The G was present at this position in the sequences of the father and 2 younger brothers. Direct sequence and single-strand conformation polymorphism analyses of polymerase chain reaction fragments revealed that the mutation at codon 49 was heterozygously present in the mother's DAX1 gene. The codon 84 is located in the first half of the DNA binding domain, and the mutation site is closer to the N-terminus than those in previously reported cases. The onset of adrenal insufficiency in the neonatal period as seen in our patient has also been reported in other patients with different DAX1 mutations, especially in a patient with DAX1 protein lacking 11 amino acids at the C-terminus. Therefore, it is less likely that position of termination codons correlate to clinical manifestations.
Hamaguchi
K
K
Department of Internal Medicine I, Oita Medical University School of Medicine, Hasama, Japan. khamaguc@oita-med.ac.jp
Arikawa
M
M
Yasunaga
S
S
Kakuma
T
T
Fukagawa
K
K
Yanase
T
T
Nawata
H
H
Sakata
T
T
D000311:Adrenal Glands / Q000002:abnormalities*; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D018388:Codon, Terminator / Q000235:genetics; D057137:DAX-1 Orphan Nuclear Receptor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000627:therapeutic use; D016368:Frameshift Mutation; D008040:Genetic Linkage; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics*
D006063:Chorionic Gonadotropin; D018388:Codon, Terminator; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D005640:Follicle Stimulating Hormone