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A novel splice site mutation in the COL4A5 gene in a Chinese female patient with rare ocular abnormalities.

ABSTRACT: PURPOSE: To describe an unusual ocular phenotype in a Chinese female patient with X-linked Alport syndrome (XLAS), and to characterize the type IV collagen alpha 5 (COL4A5) gene mutation in the patient and her son. METHODS: Detailed ophthalmologic examinations and optical coherence tomography were performed in the patient and her family members. For gene analysis of COL4A5, the entire coding region of COL4A5 mRNA from cultured skin fibroblast was analyzed by using reverse-transcription-polymerase chain reaction (RT-PCR) and direct sequencing, and genomic DNA was analyzed by using PCR and direct sequencing. RESULTS: The patient presented with progressive myopia at age 14 and bilateral giant macular holes (about 2 disc diameter) at age 28. At age 33 when presented to our hospital, slit lamp examination of the anterior segment showed bilateral anterior and posterior lenticonus; fundus photography and optical coherence tomography showed bilateral giant macular holes which were larger than photographed at age 28. Electron microscopy of renal biopsy showed irregular thinned and thickened areas of the glomerular basement membrane with splitting of the lamina densa. Her son was then found to have hematuria (at age 3), and indirect immunofluorescence of the epidermal basement membrane showed negative staining for the collagen ?5(IV) chain. However, the ophthalmological examinations of her son were unremarkable. A novel COL4A5 mutation g. 4400_4400+1del, leading to an indel in exon 45 (r. 4198delins4198+2_ 4198+72), was detected in the patient and her son. This mutation produces a shift in the reading frame, resulting in a missense sequence of 13 codons followed by a premature stop codon. Her mother was not affected with the mutation. CONCLUSIONS: Our report extends the phenotypic and genotypic spectrum of X-linked Alport syndrome.

SUBMITTER: Zhao C

PROVIDER: S-EPMC3425574 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A novel splice site mutation in the COL4A5 gene in a Chinese female patient with rare ocular abnormalities.

Zhao Chan C Wang Fang F Zhang Yanqin Y Wen Yubing Y Su Ying Y Zhang Chengfen C Sui Ruifang R Xu Fei F Ding Jie J Dong Fangtian F

Molecular vision 20120808

<h4>Purpose</h4>To describe an unusual ocular phenotype in a Chinese female patient with X-linked Alport syndrome (XLAS), and to characterize the type IV collagen alpha 5 (COL4A5) gene mutation in the patient and her son.<h4>Methods</h4>Detailed ophthalmologic examinations and optical coherence tomography were performed in the patient and her family members. For gene analysis of COL4A5, the entire coding region of COL4A5 mRNA from cultured skin fibroblast was analyzed by using reverse-transcript ...[more]

PMID: 22919268

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Project description:Patients with Disorders of Sex Development (DSD), especially those with gonadal dysgenesis and hypovirilization are at risk of developing malignant type II germ cell tumors/cancer (GCC) (seminoma/dysgerminoma and nonseminoma), with either carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesion. In 10-15% of 46,XY gonadal dysgenesis cases (i.e., Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of DNA. Frasier syndrome (FS) is characterized by gonadal dysgenesis with a high risk for development of GB as well as chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the Wilms' tumor 1 gene (WT1). Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development. Embryonic germ cells residing in this unfavourable micro-environment have an increased risk for malignant transformation. Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY. Functional in vitro studies showed no convincing protein malfunctioning. Laparoscopic examination revealed streak ovaries and a normal, but small, uterus. Pathological examination demonstrated bilateral GB and dysgerminoma, confirmed by immunohistochemistry. Occurrence of a delayed progressive kidney failure (focal segmental glomerular sclerosis) triggered analysis of WT1, revealing a pathogenic splice-site mutation in intron 9. Analysis of the SRY gene in an additional five FS cases did not reveal any mutations. The case presented shows the importance of multi-gene based diagnosis of DSD patients, allowing early diagnosis and treatment, thus preventing putative development of an invasive cancer.

Dataset Information

A novel splice site mutation in the COL4A5 gene in a Chinese female patient with rare ocular abnormalities.

Publications

A novel splice site mutation in the COL4A5 gene in a Chinese female patient with rare ocular abnormalities.

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