ABCMdb

PMID: 23443024

Jonsson F, Burstedt MS, Sandgren O, Norberg A, Golovleva I
Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family.
Eur J Hum Genet. 2013 Nov;21(11):1266-71. doi: 10.1038/ejhg.2013.23. Epub 2013 Feb 27., [PubMed]

Sentences

No. Mutations Sentence Comment

89 ABCA4 p.Asn1868Ile ABCA4 p.His423Arg Of the exonic variants, only p.N1868I and p.H423R were non-synonymous. Login to comment 90 ABCA4 p.Asn1868Ile ABCA4 p.His423Arg Bioinformatics analysis predicted p.N1868I to be possibly damaging for protein function, whereas p.H423R was predicted to be benign. Login to comment 91 ABCA4 p.Asn1868Ile Segregation analysis was done for three ABCA4 sequence variants, including p.N1868I, c.4773&#fe; 3A4G and c.5461-10T4C. Login to comment 92 ABCA4 p.Asn1868Ile The variant p.N1868I was found in homozygous form in STGD1 patient VI:10, and in heterozygous form in STGD1 patient V:4 and non-affected individuals V:6, V:7 and VI:8 (Figure 1a). Login to comment 93 ABCA4 p.Asn1868Ile To determine if p.N1868I was a common variant in our population, we tested 115 control individuals from a matched geographic region and detected 16 heterozygous carriers. Login to comment 117 ABCA4 p.Gly863Ala ABCA4 p.Asn1868Ile None of our healthy controls carried the c.5461-10T4C mutation, in line with previous observations of different population carrier frequencies.35 Interestingly, our STGD1 patients carried the sequence variant ABCA4 p.N1868I that was predicted to be possibly damaging, as well as acting as a risk-increasing factor in AMD.36 In our study, this variant was detected in almost 14% of the healthy controls, which is higher compared with the maximal frequency of 7.5% reported in a Finnish population in the 1000 Genomes project.36 It is worth mentioning that ABCA4 c.2588G4C (p.G863A), the most frequent autosomal recessive mutation in the European population, is disease causative only in combination with a severe ABCA4 mutation,32 and does not result in a STGD1 phenotype when present bi-allelic or in combination with a mild ABCA4 mutation. Login to comment 119 ABCA4 p.Asn1868Ile The same phenomena can also be applied to p.N1868I. Login to comment 124 ABCA4 p.Asn1868Ile ABCA4 p.His423Arg This result was not unexpected, as ABCA4 mRNA is expressed exclusively in retina.38 Table 3 ABCA4 sequence variants in STGD1 patient Position Nucleotide change Amino-acid change RefSNP SIFT PolyPhen Splice site effect MAF (minor allele frequency) Exon 10 c.1268A4G p.H423R rs3112831 Tolerated Benign - C &#bc; 0.246/538b Exon 28 c.4203C4A p.P1401P rs1801666 -a - - A &#bc; 0.005/12b Exon 40 c.5603A4T p.N1868I rs1801466 Possibly damaging Possibly damaging - A &#bc; 0.029/63b A &#bc; 0.139/115c Exon 40 c.5682G4C p.L1894L rs1801574 - - - G &#bc; 0.219/478b - Intron 3 c.302 &#fe; 26A4G - rs2297634 - - None T &#bc; 0.470/1026b Intron 7 c.769-32T4C - rs526016 - - None G &#bc; 0.228/497b Intron 9 c.1240-14C4T - rs4147830 - - None G &#bc; 0.477/1041b Intron 13 c.1761-54G4A - rs4147833 - - Cryptic site T &#bc; 0.377/824b Intron 26 c.3863-73_3863-64delA - rs4147892 - - None NAb Intron 33 c.4773 &#fe; 3A4G New variant - - Weak NAb G &#bc; 0.009/113c Intron 38 c.5461-10T4C rs1800728 - - Weak NAb C &#bc; 0.000/116c Intron 38 c.5461-51delA rs4147899 - - none &#bc; 0.215/469b aNot predictable. Login to comment