ABCA12 p.Gly1179Arg
| ClinVar: |
c.3535G>A
,
p.Gly1179Arg
D
, Pathogenic
|
| Predicted by SNAP2: | A: D (75%), C: D (91%), D: D (95%), E: D (95%), F: D (91%), H: D (95%), I: D (91%), K: D (95%), L: D (95%), M: D (91%), N: D (91%), P: D (91%), Q: D (95%), R: D (95%), S: D (85%), T: D (75%), V: D (91%), W: D (95%), Y: D (91%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: N, V: D, W: D, Y: D, |
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[hide] Harlequin ichthyosis: a review of clinical and mol... Arch Dermatol. 2011 Jun;147(6):681-6. Epub 2011 Feb 21. Rajpopat S, Moss C, Mellerio J, Vahlquist A, Ganemo A, Hellstrom-Pigg M, Ilchyshyn A, Burrows N, Lestringant G, Taylor A, Kennedy C, Paige D, Harper J, Glover M, Fleckman P, Everman D, Fouani M, Kayserili H, Purvis D, Hobson E, Chu C, Mein C, Kelsell D, O'Toole E
Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases.
Arch Dermatol. 2011 Jun;147(6):681-6. Epub 2011 Feb 21., [PMID:21339420]
Abstract [show]
OBJECTIVE: To assess the clinical outcomes of 45 cases of harlequin ichthyosis and review the underlying ABCA12 gene mutations in these patients. DESIGN: Multicenter, retrospective, questionnaire-based survey. SETTING: Dermatology research institute. PARTICIPANTS: Patients with harlequin ichthyosis for whom we had performed ABCA12 mutation analysis. MAIN OUTCOME MEASURES: Referring physicians were asked to complete a questionnaire using the patients' notes, detailing the clinical outcome of the affected child. In each case, the causative ABCA12 mutation was identified using standard polymerase chain reaction and sequencing techniques. RESULTS: Of the 45 cases, the ages of the survivors ranged from 10 months to 25 years, with an overall survival rate of 56%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% of cases. The early introduction of oral retinoids may improve survival, since 83% of those treated survived, whereas 76% who were not given retinoids died. Recurrent skin infections in infancy affected one-third of patients. Problems maintaining weight affected 44%. Three children developed an inflammatory arthritis, and developmental delay was reported in 32%. Mutation analysis revealed that 52% of survivors had compound heterozygous mutations, whereas all deaths were associated with homozygous mutations. CONCLUSIONS: Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. With improved neonatal care and probably the early introduction of oral retinoids, the number of survivors is increasing. Compound heterozygotes appear to have a survival advantage.
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No. Sentence Comment
177 In our series, 2 missense mutations were identified, namely V1089F in exon 23 combined with a splice site mutation in exon 33 in one patient, and G1179R (homozygous) in exon 24 of another patient.
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ABCA12 p.Gly1179Arg 21339420:177:146
status: NEW179 In our series, 2 missense mutations were identified, namely V1089F in exon 23 combined with a splice site mutation in exon 33 in one patient, and G1179R (homozygous) in exon 24 of another patient.
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ABCA12 p.Gly1179Arg 21339420:179:146
status: NEW[hide] New insight into genotype/phenotype correlations i... J Dermatol Sci. 2011 Feb;61(2):136-9. Epub 2010 Dec 1. Umemoto H, Akiyama M, Yanagi T, Sakai K, Aoyama Y, Oizumi A, Suga Y, Kitagawa Y, Shimizu H
New insight into genotype/phenotype correlations in ABCA12 mutations in harlequin ichthyosis.
J Dermatol Sci. 2011 Feb;61(2):136-9. Epub 2010 Dec 1., [PMID:21168995]
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No. Sentence Comment
35 Patient 2 carried a maternal missense mutation p.Gly1179Arg on the other locus (Fig. 1h).
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ABCA12 p.Gly1179Arg 21168995:35:49
status: NEW36 To confirm the presence of the mutation p.Gly1179Arg in Patient 2, we performed restriction enzyme digestion analysis using BclI (NEW ENGLAND BioLabs).
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ABCA12 p.Gly1179Arg 21168995:36:42
status: NEW38 The 255-bp PCR products from wild type alleles were not digested by BclI, although the PCR products from the allele with the mutation p.Gly1179Arg were digested into 173- and 82-bp fragments.
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ABCA12 p.Gly1179Arg 21168995:38:136
status: NEW40 In contrast, the PCR product after BclI digestion from the mother of Patient 2 showed 255-, 173- and 82-bp bands, which indicated that she was heterozygous for the p.Gly1179Arg missense mutation (supplementary Fig. S1).
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ABCA12 p.Gly1179Arg 21168995:40:166
status: NEW53 Patient 2 harboured two ABCA12 mutations, p.Arg1515X and p.Gly1179Arg, and both her parents were heterozygous carriers of these defects.
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ABCA12 p.Gly1179Arg 21168995:53:59
status: NEW59 The mutation p.Gly1179Arg might result in major loss of ABCA12 function and/or structure, leading to the severe phenotype in Patient 2.
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ABCA12 p.Gly1179Arg 21168995:59:15
status: NEW63 The marked difference in the clinical severity of the two patients indicated that the p.Gly1179Arg has far bigger deleterious functional effects than c.3295-2A>G.
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ABCA12 p.Gly1179Arg 21168995:63:88
status: NEW[hide] ABCA12 is the major harlequin ichthyosis gene. J Invest Dermatol. 2006 Nov;126(11):2408-13. Epub 2006 Aug 10. Thomas AC, Cullup T, Norgett EE, Hill T, Barton S, Dale BA, Sprecher E, Sheridan E, Taylor AE, Wilroy RS, DeLozier C, Burrows N, Goodyear H, Fleckman P, Stephens KG, Mehta L, Watson RM, Graham R, Wolf R, Slavotinek A, Martin M, Bourn D, Mein CA, O'Toole EA, Kelsell DP
ABCA12 is the major harlequin ichthyosis gene.
J Invest Dermatol. 2006 Nov;126(11):2408-13. Epub 2006 Aug 10., [PMID:16902423]
Abstract [show]
Harlequin ichthyosis (HI) is the most severe form of autosomal-recessive, congenital ichthyosis. Affected infants have markedly impaired barrier function and are more susceptible to infection. Abnormalities in the localization of epidermal lipids as well as abnormal lamellar granule formation are features of HI skin. Previously, we and others have shown that mutations in the ABCA12 gene encoding an adenosine triphosphate-binding cassette (ABC) transporter underlie the skin disease HI. In this study, we have sequenced the ABCA12 gene in an additional 14 patients and show that all contain mutations, with the majority being either nonsense substitution or frameshift mutations. Eleven HI patients had bi-allelic ABCA12 mutations, whereas in the remaining three HI patients in this study, ABCA12 mutations were detected on only one allele by sequencing. In addition, the one patient from the previous study where no sequence mutations were detected was screened for heterozygous deletions. A combination of oligonucleotide arrays, multiplex PCR analysis and single-nucleotide polymorphism genotyping revealed a heterozygous intragenic deletion in exon 8. These mutation data establish ABCA12 as the major HI gene.
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No. Sentence Comment
37 Although the vast majority of HI-associated ABCA12 mutations identified to date (this study) (Akiyama et al., 2005; Kelsell et al., 2005) (Figure 2) would result in a truncated protein, patient 95 was found to contain a homozygous missense substitution (G1179R) in the first transmembrane domain of ABCA12.
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ABCA12 p.Gly1179Arg 16902423:37:254
status: NEW41 (b) Denaturing high-performance liquid chromatography traces of exon 24 showing patient 95 (homozygous G1179R), the mother of patient 95 (heterozygous), and a wild-type control.
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ABCA12 p.Gly1179Arg 16902423:41:103
status: NEW44 G1179R was not detected by denaturing high-performance liquid chromatography mutation screening in one hundred unrelated controls of mixed ethnicity.
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ABCA12 p.Gly1179Arg 16902423:44:0
status: NEW75 W199* and Q228* Q354* Y377* R714* R1297* G1179R W1294* Q2161* R1881* W1744* R2203* D2363N Del 28-53 Del 23 Del T Del 8 Del G Del A Del CG Del C Ins T ABCA12 Exon 6 8 9 10 16 17 23 24 27 28 33 34 37 42 44 47 49 53 Figure 2.
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ABCA12 p.Gly1179Arg 16902423:75:41
status: NEW86 In this study, we have identified another missense substitution (G1179R) in exon 24 (homozygous in patient 95) that would substitute a glycine (uncharged polar residue) for an arginine (positively charged residue) in the first transmembrane domain of the protein.
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ABCA12 p.Gly1179Arg 16902423:86:65
status: NEW123 The primers used for denaturing high-performance liquid chromatography analysis of G1179R in exon 24 are forward primer (50 -CGGACTACAGCTTCTCGGTTA-30 ) and reverse primer (50 -AAT TTCCCACTCTGCCATTC-30 ) to amplify a product of 205 bp.
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ABCA12 p.Gly1179Arg 16902423:123:83
status: NEW132 Denaturing high-performance liquid chromatography (Transgenomic WAVE system, France) was used to assess whether the exon 24 sequence variant G1179R found in patient 95 was likely to be a mutation or a polymorphism.
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ABCA12 p.Gly1179Arg 16902423:132:141
status: NEW133 The 205 bp fragment of exon 24 was analyzed in 100 control individuals plus patient and maternal samples, which are homozygous and heterozygous for G1179R, respectively.
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ABCA12 p.Gly1179Arg 16902423:133:148
status: NEW