PMID- 10566637
OWN - NLM
STAT- MEDLINE
DCOM- 19991126
LR  - 20061115
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 84
IP  - 11
DP  - 1999 Nov
TI  - A novel compound heterozygous mutation in the steroidogenic acute regulatory
      protein gene in a patient with congenital lipoid adrenal hyperplasia.
PG  - 3983-7
AB  - Congenital lipoid adrenal hyperplasia (CLAH) is an autosomal recessive disorder
      characterized by impaired synthesis of all adrenal and gonadal steroid hormones. 
      Recently, it was reported that mutations in the steroidogenic acute regulatory
      protein (StAR) gene cause CLAH. In the present study, we have analyzed the StAR
      gene of a Japanese patient with CLAH. PCR amplification and subsequent nucleotide
      sequencing of the StAR gene and those of her parents revealed that the patient
      has a compound heterozygous mutation of this gene. In one allele, an undescribed 
      G to C transversion in codon 217, which occurred at the last base of exon 5 and
      thus altered the splice donor site sequence, apparently resulted in a
      substitution of Arg to Thr (AGG to ACG: R217T), and in the other allele, a C to T
      transition in codon 218 caused a substitution of Ala to Val (GCG to GTG: A218V), 
      which has been previously shown to abolish StAR activity. In vitro expression
      analysis of an allelic minigene that consists of exons 4-6 of the R217T mutant
      StAR gene showed that the G to C transversion in the splice donor site of exon 5 
      caused by the R217T mutation disrupts normal splicing, resulting in the complete 
      skipping of exon 5, which alters the translation reading frame of exon 6,
      introduces a stop codon at amino acid position 174, and thus impairs the
      activity. A functional expression study of the R217T replacement mutant revealed 
      that the mutant has no steroidogenesis-enhancing activity if the transcript of
      the R217T mutant allele is ever spliced normally and translated into the protein.
      From the genetic analysis of 50 healthy subjects, the novel R217T mutation was
      unlikely to be due to polymorphism. Together, these results indicate that this
      patient is a compound heterozygote for the mutation in the StAR gene (T217R and
      A218V) and that these mutations inactivate the StAR function and give rise to
      clinically manifest CLAH.
FAU - Katsumata, N
AU  - Katsumata N
AD  - Department of Endocrinology and Metabolism, National Children's Medical Research 
      Center, Tokyo, Japan.
FAU - Kawada, Y
AU  - Kawada Y
FAU - Yamamoto, Y
AU  - Yamamoto Y
FAU - Noda, M
AU  - Noda M
FAU - Nimura, A
AU  - Nimura A
FAU - Horikawa, R
AU  - Horikawa R
FAU - Tanaka, T
AU  - Tanaka T
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Codon)
RN  - 0 (Phosphoproteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (steroidogenic acute regulatory protein)
SB  - IM
MH  - Adrenal Hyperplasia, Congenital/*genetics
MH  - Alleles
MH  - Base Sequence
MH  - Codon
MH  - Exons
MH  - Female
MH  - Gene Expression
MH  - Heterozygote
MH  - Humans
MH  - Infant, Newborn
MH  - *Mutation
MH  - Phosphoproteins/*genetics
MH  - Polymerase Chain Reaction
MH  - Polymorphism, Restriction Fragment Length
MH  - RNA Splicing
MH  - RNA, Messenger/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sequence Analysis, DNA
MH  - Transfection
EDAT- 1999/11/24 00:00
MHDA- 1999/11/24 00:01
CRDT- 1999/11/24 00:00
PHST- 1999/11/24 00:00 [pubmed]
PHST- 1999/11/24 00:01 [medline]
PHST- 1999/11/24 00:00 [entrez]
AID - 10.1210/jcem.84.11.6118 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 1999 Nov;84(11):3983-7. doi: 10.1210/jcem.84.11.6118.