ABCMdb

ABCA4 p.Met1419Thr

Predicted by SNAP2:	A: D (53%), C: N (66%), D: D (66%), E: N (61%), F: N (78%), G: D (71%), H: N (66%), I: N (82%), K: N (57%), L: N (82%), N: N (53%), P: D (53%), Q: N (66%), R: N (57%), S: N (61%), T: N (66%), V: N (78%), W: D (53%), Y: N (72%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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Publications
[hide] Genetic analysis of Indian families with autosomal... Invest Ophthalmol Vis Sci. 2009 Sep;50(9):4065-71. Epub 2009 Apr 1. Singh HP, Jalali S, Narayanan R, Kannabiran C
Genetic analysis of Indian families with autosomal recessive retinitis pigmentosa by homozygosity screening.
Invest Ophthalmol Vis Sci. 2009 Sep;50(9):4065-71. Epub 2009 Apr 1., [PMID:19339744]

Abstract [show]
PURPOSE: To identify the disease-causing genes in families with autosomal recessive RP (ARRP). METHODS: Families were screened for homozygosity at candidate gene loci followed by screening of the selected gene for pathogenic mutations if homozygosity was present at a given locus. A total of 34 families were included, of which 24 were consanguineous. Twenty-three genes were selected for screening. The presence of homozygosity was assessed by genotyping flanking microsatellite markers at each locus in affected individuals. Mutations were detected by sequencing of coding regions of genes. Sequence changes were tested for presence in 100 or more unrelated normal control subjects and for cosegregation in family members. RESULTS: Homozygosity was detected at one or more loci in affected individuals of 10 of 34 families. Homozygous disease cosegregating sequence changes (two frame-shift, two missense, and one nonsense; four novel) were found in the TULP1, RLBP1, ABCA4, RPE65, and RP1 genes in 5 of 10 families. These changes were absent in 100 normal control subjects. In addition, several polymorphisms and novel variants were found. All the putative pathogenic changes were associated with severe forms of RP with onset in childhood. Associated macular degeneration was found in three families with mutations in TULP1, ABCA4, and RP1 genes. CONCLUSIONS: Novel mutations were found in different ARRP genes. Mutations were detected in approximately 15% (5/34) of ARRP families tested, suggesting involvement of other genes in the remaining families.

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No. Sentence Comment
117 This change leads to premature truncation of the ABCA4 protein and is predicted to result in complete loss of two ATP binding domains: partial loss of the first and second transmembrane domains.8 Among the other variants found in ABCA4, one novel missense change Met1419Thr (c.4256TϾC) was found (Table 3) that leads to abolition of one of the restriction sites for NlaIII in the 229-bp PCR product of exon 29 of ABCA4. Login to comment
119 Five (4.8%) of 105 control individuals were heterozygous for Met1419Thr, suggesting that it is a polymorphic variant. Login to comment
130 Novel Changes of Unknown Significance Identified in Families with ARRP Family Gene Location Change in cDNA, Protein RP126 CRB1 Exon 8 c.2715GϾA, p.Arg905Arg RP213 ABCA4 Exon 29 c.4256TϾC, p.Met1419Thr RP119 PDE6B Intron 10 c.1401ϩ31CϾA RP119 PDE6B Intron 17 c.2130-15GϾA RP160 RGR Exon 2 c.123CϾT, p.Phe41Phe RP184 RGR Intron 6 c.760-38CϾT FIGURE 1. Login to comment

[hide] Molecular testing for hereditary retinal disease a... Arch Ophthalmol. 2007 Feb;125(2):252-8. Downs K, Zacks DN, Caruso R, Karoukis AJ, Branham K, Yashar BM, Haimann MH, Trzupek K, Meltzer M, Blain D, Richards JE, Weleber RG, Heckenlively JR, Sieving PA, Ayyagari R
Molecular testing for hereditary retinal disease as part of clinical care.
Arch Ophthalmol. 2007 Feb;125(2):252-8., [PMID:17296903]

Abstract [show]
OBJECTIVE: To describe clinical molecular testing for hereditary retinal degenerations, highlighting results, interpretation, and patient education. METHODS: Mutation analysis of 8 retinal genes was performed by dideoxy sequencing. Pretest and posttest genetic counseling was offered to patients. The laboratory report listed results and provided individualized interpretation. RESULTS: A total of 350 tests were performed. The molecular basis of disease was determined in 133 of 266 diagnostic tests; the disease-causing mutations were not identified in the remaining 133 diagnostic tests. Predictive and carrier tests were requested for 9 and 75 nonsymptomatic patients with known familial mutations, respectively. CONCLUSIONS: Molecular testing can confirm a clinical diagnosis, identify carrier status, and confirm or rule out the presence of a familial mutation in nonsymptomatic at-risk relatives. Because causative mutations cannot be identified in all patients with retinal diseases, it is essential that patients are counseled before testing regarding the benefits and limitations of this emerging diagnostic tool. CLINICAL RELEVANCE: The molecular definition of the genetic basis of disease provides a unique adjunct to the clinical care of patients with hereditary retinal degenerations.

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No. Sentence Comment
86 Novel Sequence Changes Gene* Nucleotide Change Amino Acid Change Potentially Pathogenic Changes ABCA4 164A → C H55P 611G → A A204T 868C → T R290W 1699G → A V567M 1726G → C D576H 1817G → A G606A 1964T → G L725I 2173C → A F655C 2297G → A G766D 2385C → G S795R 2401G→ A A801T 3076T → C F1026L 3138T → G L1046W 3414T → C L1138P 4256T → C M1419T 4535C → A P1512H 4849G → A V1617M 4870T → G W1624G 5026A → C T1676P IVS36 - 3G→ C Splice site change 5701C → A F1900L 5885T → A V1962D 6718A → G T2240A IVS42 ϩ 1G → A Intronic change RDS 667G → C C222S VMD2 174A → G Y29C 660T → C L191P 738G → T L217F 948G → A W287X 974A → G N296D Potentially Neutral Polymorphic Changes or Changes of Uncertain Significance ABCA4 320C → A R107R 1692A → G P562P 2823T → C C941C 4869C → G G1623G 5318C → T A1773V† 5390T → C C1797C IVS15 - 13T → C Intronic change IVS24 ϩ 46A → T Intronic change IVS35 ϩ 8G → A Intronic change IVS40 - 35A → C Intronic change IVS47 ϩ 29T → C Intronic change IVS50 - 131ins/del Intronic change EFEMP1 399C → A G133G RDS IVS3 ϩ 13C → T Intronic change *The genes are described in the second footnote to Table 1. Login to comment