Genetic Study Of Angioid Streaks Patients

Objective:To identify mutations for Pseudoxanthoma elasticum(PXE) related angioid streaks(AS) patients and discuss their phenotypes and inheritance patterns.Methods:Patients who have been diagnosed of PXE related AS in PUMCH during2004to2014have been collected and were asked to recall their medical histories, family histories and finish a series of ophthalmologic examinations including visual acuity, optometry, fundus photograph and fundus autofluorescence(AF) or fundus fluorescein angiography(FFA) or ICG angiography. Blood was drawn from those who were willing to receive molecular genetics examination and50healthy people with matching age and gender as controls. DNA were extracted from the blood, primers for the31exons of the related gene ABCC6were designed and several different PCR methods including general PCR, nested PCR, gradient temperature PCR and touch-down PCR were used to amplify the target fragments, which were later sequenced by Sanger method. If a sequence change have been found, then, genetic database were searched to exclude normal SNP and reported mutation. For new ones,100chromosomes were amplified and sequenced to exclude unknown SNP. Then, use polyphen to analyze protein function, predicting the possibility of functional damage brought by the mutation. Finally, discussing phenotype and inheritance pattern based on the previous results.Results:Two sporadic patients and one family were collected. The two sporadic patients were asymptomatic. One was diagnosed of SLE and PXE at the age of31because of decreased white blood cell level, recurrent light allergy and yellow papules. AS was found during ophthalmologic examination and recessive type Ⅰ phenotype was considered. The other was diagnosed of PXE because of loose skin, recurrent bruise. AS was also found in ophthalmologic examination and dominant type Ⅱ phenotype was considered. The AS family have loose skin and yellow papules in the folding region and mainly started having visual damage and dysmorphorpsia in the middle age, thus dominant type Ⅱ phenotype was considered. All diagnosed patients showed clear, twisted brownish grey angioid streaks under fundoscopy. Six members of the family received genetic examination and a unreported new c.3378G>C (p.E1116D) missense mutation in No.24exon was detected, which lead to amino acid change from glutamic acid to Aspartic acid and possible functional damage of the protein. Based on the results above, the disease was mostly like to be inherited in an autosomal dominant (AD) way in the family and heterozygous may have incomplete penetrance, but autosomal recessive (AR) pattern should also not be excluded since there might be another mutation that was not able to be detected by PCR method. Besides, ABCC6gene was also regulated by other genes such as ABCC6P1, ABCC6P2, and influenced by factors such as hormone, environment and diet, so patients may have great clinical heterogeneity.Conclusions:PXE related AS was asymptomatic in the early stage, patients mostly started to have visual damage and dysmorphopsia in the middle age with loose skin and yellow papules. Ophthalmologic examinations show anigoid streaks which later may progress into CNV. This disease is closely related to ABCC6gene mutations, most of which are missense and nonsense mutations. It can be inherited in an AR or AD pattern, and sporadic cases can also be seen. Phenotypes were influenced by both genetic and external factors, which lead to great clinical heterogeneity.