title: Novel mutations in the CYP11B2 gene causing aldosterone synthase deficiency.
abstract: Aldosterone synthase deficiency (ASD) is a rare, autosomal recessive inherited disease. Mutations in the CYP11B2 gene are responsible for the occurrence of ASD, and the clinical manifestations of ASD vary with age. Affected infants may develop symptoms of mineralocorticoid deficiency, including clinical presentation with frequent vomiting, a variable degree of hyponatremia, hyperkalemia, and metabolic acidosis combined with poor growth, which are easily confused with several other endocrine genopathies, including pseudohypoaldosteronism type 1 and congenital adrenal hyperplasia. In the present study, whole exome sequencing (WES) was used to screen for causal variants in the genome of a Chinese pediatric patient with confusing endocrine disorder symptoms. Clinical symptoms of frequent vomiting, hyponatremia and hyperkalemia were selected as the filtering indices to analyze the WES data. Clinically relevant variants were subsequently verified using Sanger sequencing. Minigene construct analysis was used to assess the consequence of a splicing variant in the CYP11B2 gene. The compound heterozygous mutations, c.1009C>T and c.240‑1G>A, in the CYP11B2 gene were identified and confirmed, and represented novel variants. Sequence analysis results revealed that the c.1009C>T mutation at codon 337 of exon 6 was a nonsense mutation, which led to early termination of the protein translation process. In addition, further investigation of the splicing pattern in a minigene construct showed that the c.240‑1G>A mutation led to the preservation of intron 1, with the 3'‑splice site disappearing during transcriptional processing of the mRNA. Using molecular genetic assessments, the patient was finally diagnosed with ASD. Therefore, the present study identified two novel CYP11B2 gene mutations in a Chinese patient with ASD, indicating exome sequencing as an effective diagnostic tool for rare endocrine-metabolic diseases.
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Niu
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D044466:Asian People; D001483:Base Sequence; D002681:China; D018389:Codon, Nonsense; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D005091:Exons; D057809:HEK293 Cells; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000175:diagnosis / Q000235:genetics*; D012326:RNA Splicing; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D019405:Cytochrome P-450 CYP11B2