Compound heterozygosity of a novel Q73X mutation and a known R141X mutation in CYP11B1 resulting in 11β-hydroxylase deficiency in a Chinese boy with congenital adrenal hyperplasia

Steroid 11 beta-hydroxylase deficiency (1113- OHD), which is caused by mutations of the CYP11B1 gene, is the second leading cause of congenital adrenal hyperplasia (CAH), an autosomal recessive inherited disorder. Here, we report a case of classic 11 beta-OHD in a Chinese boy characterized by hypertension, penile enlargement, skin pigmentation, and acne. Molecular analysis of CYP11B1 revealed that the patient was compound heterozygous for a c.217C > T (p.Q73X) mutation in exon 1 and a c.421C > T (p.R141X) mutation in exon 3. His parents carried the novel c.217C > T (p.Q73X) mutation and the prevalent c.421C > T (p.R141X) mutation. Furthermore, we identified a novel 217-bp substitution mutation (Q73X) in CYP11B1 that generates a truncated protein without biological activity, which is likely to be pathogenic. Pursuant to the phenotype of the proband and his family, the Q73X mutation is inferred to exacerbate the disease burden of the R141X mutation, a known pathogenic variant. To further explore this possibility, selecting the x-ray structure of human CYP11B2 as a template, we built three-dimensional homologous models of the normal and mutant proteins. In the mutant model, a change from a helix to terminal structure in amino acids 73 and 141 occurred that affected the binding capacity of CYP11B1 with heme and impaired 11 beta-hydroxylase activity. Taken together, our findings expand the spectrum of known mutations leading to 11 beta-OHD and provide evidence to study genotype-phenotype concordance, confirm early diagnosis and treatment of 11 beta-OHD, and prevent most complications.

Automated summary

We reported a case of classic 11 beta-hydroxylase deficiency in a Chinese boy with compound heterozygous mutations in the CYP11B1 gene. A novel mutation, Q73X, was identified as exacerbating the disease burden in addition to the known pathogenic variant R141X. Three-dimensional homologous models confirmed that the mutant protein affected the binding capacity of CYP11B1 with heme and impaired 11 beta-hydroxylase activity.