Dataset Information

A novel mutation and phenotypes in phosphodiesterase 6 deficiency.

ABSTRACT:

Purpose

To develop a systematic approach for the molecular diagnosis of retinitis pigmentosa (RP) and to report new genotype-phenotype correlations for phosphodiesterase 6 (PDE6)-based RP mutations.

Design

Clinical and molecular studies on a retrospective case series.

Methods

We screened 40 unrelated RP patients with an autosomal recessive RP microarray. Individuals with RP caused by PDE6 deficiency underwent genetic segregation and phenotype analysis.

Results

A disease-associated allele was identified in 32% of patients. Two probands (5%) had PDE6 mutations. The first proband was a compound heterozygote for known R102C and N216S alleles in PDE6A (MIM#180071). Pedigree analysis determined that the N216S variant was benign and direct sequencing discovered a novel, S303C allele. The second proband had a homozygous D600N mutation in the PDE6B gene (MIM#180072). Visual acuities of PDE6-deficient patients ranged from 20/40 to 20/200. Clinical studies showed unusual vitreomacular traction, cystoid macular edema, macular atrophy, and ring hyperfluorescence in PDE6-deficient patients. Such extensive vitreoretinal degeneration is not characteristic of photoreceptor-specific enzyme deficiencies.

Conclusion

High-throughput deoxyribonucleic acid microarray chips can be used in combination with clinical imaging to precisely characterize patients with RP. Identifying the precise mutation in RP may become the standard of care as gene therapy emerges.

SUBMITTER: Tsang SH

PROVIDER: S-EPMC2593460 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Publications

A novel mutation and phenotypes in phosphodiesterase 6 deficiency.

Tsang Stephen H SH Tsui Irena I Chou Chai Lin CL Zernant Jana J Haamer Eneli E Iranmanesh Reza R Tosi Joaquin J Allikmets Rando R

American journal of ophthalmology 20080823 5

<h4>Purpose</h4>To develop a systematic approach for the molecular diagnosis of retinitis pigmentosa (RP) and to report new genotype-phenotype correlations for phosphodiesterase 6 (PDE6)-based RP mutations.<h4>Design</h4>Clinical and molecular studies on a retrospective case series.<h4>Methods</h4>We screened 40 unrelated RP patients with an autosomal recessive RP microarray. Individuals with RP caused by PDE6 deficiency underwent genetic segregation and phenotype analysis.<h4>Results</h4>A dise ...[more]

PMID: 18723146

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Project description:BACKGROUND: Aromatase deficiency is a rare, autosomal recessive disorder of which there are approximately twenty four case reports. The aromatase enzyme is crucial in the biosynthesis of oestrogens from androgens. The phenotype of aromatase deficiency therefore is the result of androgen excess and oestrogen deficiency in the absence of normal aromatase activity. We report the first case of aromatase deficiency diagnosed in a female adult, at the age of 32 years, due to a novel duplication in the aromatase gene. CASE PRESENTATION: A 32 year old Indian woman presented with a history of gender assignment difficulties at birth, lack of pubertal development, osteopaenia with fracture and tall stature. She had central obesity, impaired fasting glucose and borderline hypertension. Past examinations had revealed partial fusion of urethra and vagina, hypoplastic uterus and streak ovaries. The ovaries had been excised due to malignant risk after an initial clinical diagnosis of Turner's syndrome with Y mosaicism. Oestrogen replacement commenced shortly after her fracture, in adulthood. After reassessment, aromatase deficiency was diagnosed. Sequencing of the coding exons of the aromatase (CYP19A1; OMIM 109710) gene revealed a novel 27-base duplication in exon 8 (p.Ala306_Ser314dup). This duplication, occurring within the aromatase ?-helix, would be likely to disrupt substrate (androgen) and cofactor (protoporphyrin IX) binding, resulting in a lack of oestrogen synthesis. CONCLUSIONS: We report a female with a phenotype compatible with aromatase deficiency which was unrecognised until adulthood and found she had a novel duplication in CYP19A1. Previous case reports have described polycystic ovarian morphology, especially in childhood and adolescence, but never streak ovaries. This may reflect the few adult cases reported, that aromatase deficiency in females is generally diagnosed at birth and oestrogen treatment commences decades earlier than occurred in our patient. Streak ovaries are consistent with the phenotype of the aromatase knockout mouse followed through adulthood. The observed clinical features of obesity, dysglycaemia and hypertension, are compatible with the observation that lack of a counterbalancing effect of oestrogen on tissue androgens until adulthood may lead to a metabolic syndrome phenotype. This report broadens the spectra of phenotype and genetic mutations underlying this rare disorder.

Dataset Information

A novel mutation and phenotypes in phosphodiesterase 6 deficiency.

Purpose

Design

Methods

Results

Conclusion

Publications

A novel mutation and phenotypes in phosphodiesterase 6 deficiency.

Similar Datasets

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