Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene

Nguyen, Huy-Hoang; Eiden-Plach, Antje; Hannemann, Frank; Małunowicz, E; Hartmann, Michaela F.; Wudy, Stefan A.; Bernhardt, Rita

doi:10.1016/j.jsbmb.2015.10.011

Cited by 21 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been demonstrated before that the design of a minigene construct can influence the splicing outcome. Two recent studies that analyzed the very same canonical splice site mutation in the CYP11B1 gene but utilized different minigene amplicons (one containing only two exons, the other four exons) observed very different missplicing outcomes: whereas the shorter minigene amplicon revealed intron retention for the mutant allele, the longer minigene amplicon led to either skipping of one exon or two exons 35 , 36 . To add even more complexity, we observed a small amount of correctly spliced transcript for the c.2040 + 5 G > T variant which might lead to residual protein function.…”

Section: Discussionmentioning

confidence: 99%

CDHR1 mutations in retinal dystrophies

Štingl

Mayer

Llavona

et al. 2017

Sci Rep

View full text Add to dashboard Cite

We report ophthalmic and genetic findings in patients with autosomal recessive retinitis pigmentosa (RP), cone-rod dystrophy (CRD) or cone dystrophy (CD) harboring potential pathogenic variants in the CDHR1 gene. Detailed ophthalmic examination was performed in seven sporadic and six familial subjects. Mutation screening was done using a customized next generation sequencing panel targeting 105 genes implicated in inherited retinal disorders. In one family, homozygosity mapping with subsequent candidate gene analysis was performed. Stringent filtering for rare and potentially disease causing variants following a model of autosomal recessive inheritance led to the identification of eleven different CDHR1 variants in nine index cases. All variants were novel at the time of their identification. In silico analyses confirmed their pathogenic potential. Minigene assays were performed for two non-canonical splice site variants and revealed missplicing for the mutant alleles. Mutations in CDHR1 are a rare cause of retinal dystrophy. Our study further expands the mutational spectrum of this gene and the associated clinical presentation.

show abstract

Section: Discussionmentioning

confidence: 99%

CDHR1 mutations in retinal dystrophies

Štingl

Mayer

Llavona

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…However, the onset of hypertension is variable in 11 β-hydroxylase deficiency, making it a less reliable clue. [7] Although suppressed plasma renin can be another useful clue, it may not be helpful always (as observed in patient 1). However, as documented in the steroid profile of patient 1 and 2, a suppressed plasma aldosterone can be a useful clue.…”

Section: Discussionmentioning

confidence: 99%

Utility of a commercially available blood steroid profile in endocrine practice

Sarathi

Atluri

Pradeep

et al. 2019

Indian J Endocr Metab

View full text Add to dashboard Cite

Background: A blood steroid profile has recently become available on commercial basis in India. In this study, we report our initial experience with the use of steroid profile in the evaluation of disorders of sex development (DSD) and suspected cases of congenital adrenal hyperplasia (CAH) and discuss the potential scenarios in endocrine practice that may benefit from this steroid profile. Materials and Methods: The study included six subjects. Patient 1 was a 46, XX girl who presented with peripubertal virilization, patient 2 was a girl who presented with normal pubertal development, secondary amenorrhea, and virilization, and patient 3 was a girl who presented with primary amenorrhea and virilization. These three patients were suspected to have CAH but had non-diagnostic serum 17 OH-progesterone levels. Patient 4 and 5 were 46, XY reared as girls who presented with primary amenorrhea alone and primary amenorrhea and virilization, respectively, and sixth subject was a heathy volunteer. All subjects were evaluated with blood steroid profile by Liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: Patient 1 and 2 were diagnosed to have 11 β-hydroxylase deficiency by using the steroid profile. Patient 3 was suspected to have CAH, but the steroid profile excluded the diagnosis and helped to confirm the diagnosis as polycystic ovary syndrome. In patient 4 and patient 5, although steroid profile ruled out the possibility of steroidogenesis defects, it did not help to reach at the specific diagnosis. Conclusion: The blood steroid profile used in this study is most useful for the diagnosis of 11 β-hydroxylase deficiency. The utility of this test is limited in the evaluation of 46, XY patients with under-virilization.

show abstract

“…Most reported CYP11B1 mutations are located in exons 6, 7, and 8 and 70 % of amino acid sequences in these exons are identical in human, ox, rat, and mouse, suggesting that exons 6–8 are essential for the enzymatic activity of CYP11B1 [ 15 ]. Recently, Nguyen et al [ 9 ] studied a minigene experiment of this same mutation. Nonetheless, the authors designed a shorter minigene construct which had only exon 7, intron 7, and exon 8.…”

Section: Discussionmentioning

confidence: 99%

Splicing analysis of CYP11B1 mutation in a family affected with 11β-hydroxylase deficiency: case report

et al. 2016

View full text Add to dashboard Cite

BackgroundCongenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency (11β-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11β-OHD and analyze the effects of a splicing mutation.Case presentationA 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty. Hormonal studies suggested 11β-OHD. Mutation analysis was performed by PCR followed by Sanger sequencing of the entire coding regions and their flanking introns of the CYP11B1 gene. Mutation analysis showed that both patients were compound heterozygous for IVS7 + 1G > A, and c.421C > T. Although the identified mutations have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. A minigene assay was used to determine the effects of the splicing mutation. The constructs containing either the wild-type or the splice-site mutant CYP11B1 genomic DNA of exons-introns 6–9 were transfected into COS-7 cells; subsequently, RNA splicing was assessed by reversed transcribed-PCR of CYP11B1 complementary DNA. The minigene assay revealed that the IVS7 + 1G > A mutation resulted in two shorter incorrectly spliced products; one skipping the exon 7 and the other skipping the exons 7–8. The c.421C > T mutation leads to the introduction of a premature stop codon at residue 141 (p.R141X). These mutations are expected to code non-functional proteins.ConclusionCompound heterozygous mutations (IVS7 + 1G > A and p.R141X) in the CYP11B1 gene were found to cause 11β-OHD. The IVS7 + 1G > A mutation causes aberrant splicing of CYP11B1 leading to exon skipping. This finding could facilitate the future novel therapies targeted on splicing modulation to treat human disease.

show abstract

Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene

Cited by 21 publications

References 24 publications

CDHR1 mutations in retinal dystrophies

CDHR1 mutations in retinal dystrophies

Utility of a commercially available blood steroid profile in endocrine practice

Splicing analysis of CYP11B1 mutation in a family affected with 11β-hydroxylase deficiency: case report

Contact Info

Product

Resources

About