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Title: Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia

Abstract

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) most commonly carry an A-G transition at nucleotide 656 (nt 656 A{r_arrow}G), causing abnormal splicing of exons 2 and 3 in CYP21, the gene encoding active steroid 21-hydroxylase. Affected infants are severely deficient in cortisol and aldosterone, and usually come to medical attention during the neonatal period. We report on 2 affected boys, homozygous for the nt 656 mutation, who thrived in early infancy, but suffered salt-wasting crises unusually late in infancy, at 3.5 and 5.5 months, respectively. Laboratory studies at presentation showed hyponatremia, hyperkalemia, dehydration, and acidosis; serum aldosterone was low in spite of markedly elevated plasma renin activity. Basal 17-hydroxyprogesterone levels were only moderately elevated, yet the stimulated levels were more typical of severe, classic CAH due to 21-hydroxylase deficiency. Genomic DNA from the patients was analyzed. Southern blot showed no major deletions or rearrangements. CYP21-specific amplification by polymerase chain reaction, coupled with allele-specific hybridization using wild-type and mutant probes at each of 9 sites for recognized disease-causing mutations, revealed a single, homozygous mutation in each patient: nt 656 A{r_arrow}G. These results were confirmed by sequence analysis. We conclude that the common nt 656 A{r_arrow}G mutation is sometimes associated with delayedmore » phenotypic expression of SW-CAH. We speculate that variable splicing of the mutant CYP21 may modify the clinical manifestation of this disease. 22 refs., 1 fig., 1 tab.« less

Authors:
; ;  [1]
  1. North Shore Univ. Hospital, Manhasset, NY (United States); and others
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
105212
Resource Type:
Journal Article
Journal Name:
American Journal of Medical Genetics
Additional Journal Information:
Journal Volume: 57; Journal Issue: 3; Other Information: PBD: 3 Jul 1995
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; INFANTS; PHENOTYPE; HEREDITARY DISEASES; METABOLIC DISEASES; CONGENITAL DISEASES; GENES; GENE MUTATIONS; SPLICING; STEROID HORMONES; SODIUM; HOMEOSTASIS; PROBES; NUCLEOTIDES; POLYMERASE CHAIN REACTION; DNA HYBRIDIZATION; DNA SEQUENCING

Citation Formats

Kohn, B, Patel, S V, and Pelczar, J V. Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia. United States: N. p., 1995. Web. doi:10.1002/ajmg.1320570318.
Kohn, B, Patel, S V, & Pelczar, J V. Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia. United States. https://doi.org/10.1002/ajmg.1320570318
Kohn, B, Patel, S V, and Pelczar, J V. 1995. "Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia". United States. https://doi.org/10.1002/ajmg.1320570318.
@article{osti_105212,
title = {Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia},
author = {Kohn, B and Patel, S V and Pelczar, J V},
abstractNote = {Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) most commonly carry an A-G transition at nucleotide 656 (nt 656 A{r_arrow}G), causing abnormal splicing of exons 2 and 3 in CYP21, the gene encoding active steroid 21-hydroxylase. Affected infants are severely deficient in cortisol and aldosterone, and usually come to medical attention during the neonatal period. We report on 2 affected boys, homozygous for the nt 656 mutation, who thrived in early infancy, but suffered salt-wasting crises unusually late in infancy, at 3.5 and 5.5 months, respectively. Laboratory studies at presentation showed hyponatremia, hyperkalemia, dehydration, and acidosis; serum aldosterone was low in spite of markedly elevated plasma renin activity. Basal 17-hydroxyprogesterone levels were only moderately elevated, yet the stimulated levels were more typical of severe, classic CAH due to 21-hydroxylase deficiency. Genomic DNA from the patients was analyzed. Southern blot showed no major deletions or rearrangements. CYP21-specific amplification by polymerase chain reaction, coupled with allele-specific hybridization using wild-type and mutant probes at each of 9 sites for recognized disease-causing mutations, revealed a single, homozygous mutation in each patient: nt 656 A{r_arrow}G. These results were confirmed by sequence analysis. We conclude that the common nt 656 A{r_arrow}G mutation is sometimes associated with delayed phenotypic expression of SW-CAH. We speculate that variable splicing of the mutant CYP21 may modify the clinical manifestation of this disease. 22 refs., 1 fig., 1 tab.},
doi = {10.1002/ajmg.1320570318},
url = {https://www.osti.gov/biblio/105212}, journal = {American Journal of Medical Genetics},
number = 3,
volume = 57,
place = {United States},
year = {Mon Jul 03 00:00:00 EDT 1995},
month = {Mon Jul 03 00:00:00 EDT 1995}
}