TY - JOUR
T1 - A high rate of novel CYP11B1 mutations in Saudi Arabia
AU - Alzahrani, Ali S.
AU - Alswailem, Meshael M.
AU - Murugan, Avaniyapuram Kannan
AU - Saqer Hamad Alhmaidah, Dhuha
AU - Capper, Cameron P.
AU - Auchus, Richard J.
AU - Qasem, Ebtesam
AU - Alzahrani, Ohoud S.
AU - Al-Sagheir, Afaf
AU - Bin-Abbas, Bassam
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Despite ethnic variation, 11 β-hydroxylase deficiency (11β-OHD) has generally been considered the second most common subtype of congenital adrenal hyperplasia (CAH). We report a high rate of novel mutations in this gene (CYP11B1) in patients from Saudi Arabia. We studied 16 patients with 11β-OHD from 8 unrelated families. DNA was isolated from peripheral blood. The 9 exons and exon-intron boundaries of CYP11B1 were PCR-amplified and directly sequenced. The novel mutations were functionally characterized using subcloning, in vitro mutagenesis, cell transfection and 11-deoxycortisol: cortisol conversion assays. Six mutations were found in these 8 unrelated families. Three of these mutations are completely novel and two have just been recently described as novel mutations from the same population. These include a single nucleotide insertion mutation in codon 18 (c.53_54insT) leading to frameshift and truncation in 4 siblings, a novel mutation (c.1343G>C, p.R448P) in 3 unrelated families, a novel mutation (c.1394A>T, p.H465L) in 2 siblings, a novel mutation (c.617G>T, p.G206V) in 1 patient, and a recently described non-sense novel mutation (c.780G>A, p.W260X) in another patient. Out of the 6 mutations described in this report, only one mutation (p.Q356X) was reported previously. In vitro functional testing of the 3 missense and nonsense novel mutations revealed complete loss of the 11 hydroxylase activity. We conclude that 11 β-OHD in Saudi Arabia has a unique genotype with a high rate of novel mutations. The novel p. R448P mutation is the most common mutation in this highly inbred population.
AB - Despite ethnic variation, 11 β-hydroxylase deficiency (11β-OHD) has generally been considered the second most common subtype of congenital adrenal hyperplasia (CAH). We report a high rate of novel mutations in this gene (CYP11B1) in patients from Saudi Arabia. We studied 16 patients with 11β-OHD from 8 unrelated families. DNA was isolated from peripheral blood. The 9 exons and exon-intron boundaries of CYP11B1 were PCR-amplified and directly sequenced. The novel mutations were functionally characterized using subcloning, in vitro mutagenesis, cell transfection and 11-deoxycortisol: cortisol conversion assays. Six mutations were found in these 8 unrelated families. Three of these mutations are completely novel and two have just been recently described as novel mutations from the same population. These include a single nucleotide insertion mutation in codon 18 (c.53_54insT) leading to frameshift and truncation in 4 siblings, a novel mutation (c.1343G>C, p.R448P) in 3 unrelated families, a novel mutation (c.1394A>T, p.H465L) in 2 siblings, a novel mutation (c.617G>T, p.G206V) in 1 patient, and a recently described non-sense novel mutation (c.780G>A, p.W260X) in another patient. Out of the 6 mutations described in this report, only one mutation (p.Q356X) was reported previously. In vitro functional testing of the 3 missense and nonsense novel mutations revealed complete loss of the 11 hydroxylase activity. We conclude that 11 β-OHD in Saudi Arabia has a unique genotype with a high rate of novel mutations. The novel p. R448P mutation is the most common mutation in this highly inbred population.
KW - Ambiguous genitalia
KW - Congenital adrenal hyperplasia
KW - CYP11B1
KW - Mutations
UR - http://www.scopus.com/inward/record.url?scp=85030637064&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2017.09.018
DO - 10.1016/j.jsbmb.2017.09.018
M3 - Article
C2 - 28962970
AN - SCOPUS:85030637064
VL - 174
SP - 217
EP - 224
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
SN - 0960-0760
ER -