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A Novel Mutation in the CYP11B1 Gene Causes Steroid 11β-Hydroxylase Deficient Congenital Adrenal Hyperplasia with Reversible Cardiomyopathy.

Alqahtani MA, Shati AA, Zou M, Alsuheel AM, Alhayani AA, Al-Qahtani SM, Gilban HM, Meyer BF, Shi Y - Int J Endocrinol (2015)

Bottom Line: A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients.The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity.In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Aseer Central Hospital, Abha 62523, Saudi Arabia.

ABSTRACT
Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency is the second most common form of CAH, resulting from a mutation in the CYP11B1 gene. Steroid 11β-hydroxylase deficiency results in excessive mineralcorticoids and androgen production leading to hypertension, precocious puberty with acne, enlarged penis, and hyperpigmentation of scrotum of genetically male infants. In the present study, we reported 3 male cases from a Saudi family who presented with penile enlargement, progressive darkness of skin, hypertension, and cardiomyopathy. The elder patient died due to heart failure and his younger brothers were treated with hydrocortisone and antihypertensive medications. Six months following treatment, cardiomyopathy disappeared with normal blood pressure and improvement in the skin pigmentation. The underlying molecular defect was investigated by PCR-sequencing analysis of all coding exons and intron-exon boundary of the CYP11B1 gene. A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients. The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity. Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260 (∗) ) was reported in a patient with papillary thyroid cancer (COSMIC database). In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH. Cardiomyopathy and cardiac failure can be reversed by early diagnosis and treatment.

No MeSH data available.


Related in: MedlinePlus

A novel nonsense mutation in the human CYP11B1 gene. (a) Pedigree of a large Saudi family with CYP11B1 gene mutation. Three brothers are diagnosed with steroid 11β-hydroxylase deficient congenital adrenal hyperplasia. One died at 30 months of age due to heart failure. Both parents and three siblings are unaffected. (b) Sequence analysis shows a biallelic c.780 G>A mutation in exon 4 of the CYP11B1 gene in both patients from the family. The mutation creates a premature stop codon TGA. The mutation is indicated by an arrow. The parents refused to donate blood for genetic testing, but they are likely heterozygous carriers.
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fig2: A novel nonsense mutation in the human CYP11B1 gene. (a) Pedigree of a large Saudi family with CYP11B1 gene mutation. Three brothers are diagnosed with steroid 11β-hydroxylase deficient congenital adrenal hyperplasia. One died at 30 months of age due to heart failure. Both parents and three siblings are unaffected. (b) Sequence analysis shows a biallelic c.780 G>A mutation in exon 4 of the CYP11B1 gene in both patients from the family. The mutation creates a premature stop codon TGA. The mutation is indicated by an arrow. The parents refused to donate blood for genetic testing, but they are likely heterozygous carriers.

Mentions: To identify the underlying genetic defects leading to steroid 11β-hydroxylase deficiency, we sequenced the entire coding region and intron-exon boundaries of the CYP11B1 gene in both patients. A novel biallelic mutation in the CYP11B1 gene was found in both patients. The mutation c.780 G>A created a premature stop codon at amino acid 260 (p.W260∗), resulting in functional inactivation of the CYP27B1 gene (Figure 2). Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260∗) was reported in a patient with papillary thyroid cancer (COSMIC data base). The significance of the mutation in thyroid cancer remains to be determined. The parents and three unaffected siblings (two brothers and one sister) refused to donate blood samples for genetic test, which prevented us from performing a familial genetic analysis. However, the parents are likely heterozygous carriers.


A Novel Mutation in the CYP11B1 Gene Causes Steroid 11β-Hydroxylase Deficient Congenital Adrenal Hyperplasia with Reversible Cardiomyopathy.

Alqahtani MA, Shati AA, Zou M, Alsuheel AM, Alhayani AA, Al-Qahtani SM, Gilban HM, Meyer BF, Shi Y - Int J Endocrinol (2015)

A novel nonsense mutation in the human CYP11B1 gene. (a) Pedigree of a large Saudi family with CYP11B1 gene mutation. Three brothers are diagnosed with steroid 11β-hydroxylase deficient congenital adrenal hyperplasia. One died at 30 months of age due to heart failure. Both parents and three siblings are unaffected. (b) Sequence analysis shows a biallelic c.780 G>A mutation in exon 4 of the CYP11B1 gene in both patients from the family. The mutation creates a premature stop codon TGA. The mutation is indicated by an arrow. The parents refused to donate blood for genetic testing, but they are likely heterozygous carriers.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4525762&req=5

fig2: A novel nonsense mutation in the human CYP11B1 gene. (a) Pedigree of a large Saudi family with CYP11B1 gene mutation. Three brothers are diagnosed with steroid 11β-hydroxylase deficient congenital adrenal hyperplasia. One died at 30 months of age due to heart failure. Both parents and three siblings are unaffected. (b) Sequence analysis shows a biallelic c.780 G>A mutation in exon 4 of the CYP11B1 gene in both patients from the family. The mutation creates a premature stop codon TGA. The mutation is indicated by an arrow. The parents refused to donate blood for genetic testing, but they are likely heterozygous carriers.
Mentions: To identify the underlying genetic defects leading to steroid 11β-hydroxylase deficiency, we sequenced the entire coding region and intron-exon boundaries of the CYP11B1 gene in both patients. A novel biallelic mutation in the CYP11B1 gene was found in both patients. The mutation c.780 G>A created a premature stop codon at amino acid 260 (p.W260∗), resulting in functional inactivation of the CYP27B1 gene (Figure 2). Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260∗) was reported in a patient with papillary thyroid cancer (COSMIC data base). The significance of the mutation in thyroid cancer remains to be determined. The parents and three unaffected siblings (two brothers and one sister) refused to donate blood samples for genetic test, which prevented us from performing a familial genetic analysis. However, the parents are likely heterozygous carriers.

Bottom Line: A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients.The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity.In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Aseer Central Hospital, Abha 62523, Saudi Arabia.

ABSTRACT
Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency is the second most common form of CAH, resulting from a mutation in the CYP11B1 gene. Steroid 11β-hydroxylase deficiency results in excessive mineralcorticoids and androgen production leading to hypertension, precocious puberty with acne, enlarged penis, and hyperpigmentation of scrotum of genetically male infants. In the present study, we reported 3 male cases from a Saudi family who presented with penile enlargement, progressive darkness of skin, hypertension, and cardiomyopathy. The elder patient died due to heart failure and his younger brothers were treated with hydrocortisone and antihypertensive medications. Six months following treatment, cardiomyopathy disappeared with normal blood pressure and improvement in the skin pigmentation. The underlying molecular defect was investigated by PCR-sequencing analysis of all coding exons and intron-exon boundary of the CYP11B1 gene. A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients. The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity. Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260 (∗) ) was reported in a patient with papillary thyroid cancer (COSMIC database). In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH. Cardiomyopathy and cardiac failure can be reversed by early diagnosis and treatment.

No MeSH data available.


Related in: MedlinePlus