ABCMdb

ABCB6 p.Leu811Val

ClinVar:	c.2431C>G , p.Leu811Val D , Pathogenic
Predicted by SNAP2:	A: D (85%), C: D (80%), D: D (95%), E: D (95%), F: D (85%), G: D (95%), H: D (95%), I: D (80%), K: D (95%), M: D (85%), N: D (95%), P: D (95%), Q: D (91%), R: D (91%), S: D (91%), T: D (91%), V: D (80%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] ABCB6 mutations cause ocular coloboma. Am J Hum Genet. 2012 Jan 13;90(1):40-8. Epub 2012 Jan 5. Wang L, He F, Bu J, Zhen Y, Liu X, Du W, Dong J, Cooney JD, Dubey SK, Shi Y, Gong B, Li J, McBride PF, Jia Y, Lu F, Soltis KA, Lin Y, Namburi P, Liang C, Sundaresan P, Paw BH, Li W, Li DY, Phillips JD, Yang Z
ABCB6 mutations cause ocular coloboma.
Am J Hum Genet. 2012 Jan 13;90(1):40-8. Epub 2012 Jan 5., [PMID:22226084]

Abstract [show]
Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure. This disorder displays genetic and clinical heterogeneity. Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma. The Leu811Val mutation was identified in seven affected members of the family and was absent in six unaffected members from three generations. A LOD score of 3.2 at theta = 0 was calculated for the mutation identified in this family. Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC. These two mutations were not present in the ethnically matched control populations. Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells. RT-PCR of ABCB6 mRNA in human cell lines and tissue indicated that ABCB6 is expressed in the retinae and RPE cells. Using zebrafish, we show that abcb6 is expressed in the eye and CNS. Morpholino knockdown of abcb6 in zebrafish produces a phenotype characteristic of coloboma and replicates the clinical phenotype observed in our index cases. The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function. Our results demonstrate that ABCB6 mutations cause ocular coloboma.

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No. Sentence Comment
3 The Leu811Val mutation was identified in seven affected members of the family and was absent in six unaffected members from three generations. Login to comment
28 Mutations in ABCB6 and Clinical Photographs of Patients with Coloboma (A) Pedigree and segregation of the Leu811Val mutation in the Chinese family affected by coloboma. Login to comment
32 (F-H) Two mutations in ABCB6 and their sequencing tracing, including Leu811Val (F) in the Chinese family affected by coloboma and Ala57Thr (G) in the three Indian patients who have microphthalmia and coloboma. Login to comment
64 The Leu811Val and Ala57Thr mutations were introduced into the WT ABCB6 pcDNA3.1(þ)/Myc-His A construct by PCR-based site-directed mutagenesis. Login to comment
87 The nucleotide alteration results in a change of leucine to valine at position 811 (Leu811Val) of ABCB6 (Figure 1F). Login to comment
140 Transcription factors such as PAX6, SOX2, OTX2, RAX, and SIX3 interact and provide transcriptional oversight to other coloboma-associated mutations in genes that play a pivotal role in spatial and temporal development of the eye.8,10-12,15,19 Here, we identified two mutations (Leu811Val and Ala57Thr) in ABCB6. Login to comment
154 These phenotypes can be rescued by the coinjection of WT ABCB6 mRNA (G and H), but the phenotypes could not be rescued by coinjection of the human mRNA containing either the Leu811Val (I and J) or the Ala57Thr (K and L) mutation. Login to comment

[hide] Novel mutations of ABCB6 associated with autosomal... PLoS One. 2013 Nov 5;8(11):e79808. doi: 10.1371/journal.pone.0079808. eCollection 2013. Cui YX, Xia XY, Zhou Y, Gao L, Shang XJ, Ni T, Wang WP, Fan XB, Yin HL, Jiang SJ, Yao B, Hu YA, Wang G, Li XJ
Novel mutations of ABCB6 associated with autosomal dominant dyschromatosis universalis hereditaria.
PLoS One. 2013 Nov 5;8(11):e79808. doi: 10.1371/journal.pone.0079808. eCollection 2013., [PMID:24224009]

Abstract [show]
OBJECTIVE: Dyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH. METHODS: Skin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals. RESULTS: Histopathological analysis showed melanocytes in normal control's skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6. CONCLUSION: Our data add new variants to the repertoire of ABCB6 mutations with DUH.

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Sentences [show]
No. Sentence Comment
133 Heterozygous missense mutations (p.L811V and p.A57T) in ABCB6 caused iris coloboma, aniridia, chorioretinal coloboma [14]. Login to comment

[hide] Genome-wide linkage, exome sequencing and function... PLoS One. 2014 Feb 3;9(2):e87250. doi: 10.1371/journal.pone.0087250. eCollection 2014. Liu H, Li Y, Hung KK, Wang N, Wang C, Chen X, Sheng D, Fu X, See K, Foo JN, Low H, Liany H, Irwan ID, Liu J, Yang B, Chen M, Yu Y, Yu G, Niu G, You J, Zhou Y, Ma S, Wang T, Yan X, Goh BK, Common JE, Lane BE, Sun Y, Zhou G, Lu X, Wang Z, Tian H, Cao Y, Chen S, Liu Q, Liu J, Zhang F
Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria.
PLoS One. 2014 Feb 3;9(2):e87250. doi: 10.1371/journal.pone.0087250. eCollection 2014., [PMID:24498303]

Abstract [show]
BACKGROUND: As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH) had remained unclear until recently when ABCB6 was reported as a causative gene of DUH. METHODOLOGY: We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation. RESULTS: Genome-wide linkage (assuming autosomal dominant inheritance mode) and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val) that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val) and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys) in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them. CONCLUSION: Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma.

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No. Sentence Comment
66 Discussion A recent publication showed that two missense mutations of ABCB6 (c.2431C.G; p.Leu811Val and c.169G.A; p.Ala57Thr) caused ocular coloboma [10]. Login to comment
82 The two DUH mutations lie in the ABC transmembrane domain, whereas one coloboma mutation (c.2431C.G; p.Leu811Val) located in the transporter-like domain, and the other one (c.169G.A; p.Ala57Thr) did not lie in any established domain (Figure 2 C). Login to comment
103 C: ABCB6 exon structure, where c.964A.C; p.S322L and c.1358C.T; p.A453V are DUH mutations identified in this paper, c.169G.A; p.A57T and c.2431C.G; p.L811V are coloboma mutations7 . Login to comment

[hide] Novel missense mutations of ABCB6 in two chinese f... J Dermatol Sci. 2014 Dec;76(3):255-8. doi: 10.1016/j.jdermsci.2014.08.015. Epub 2014 Sep 11. Lu C, Liu J, Liu F, Liu Y, Ma D, Zhang X
Novel missense mutations of ABCB6 in two chinese families with dyschromatosis universalis hereditaria.
J Dermatol Sci. 2014 Dec;76(3):255-8. doi: 10.1016/j.jdermsci.2014.08.015. Epub 2014 Sep 11., [PMID:25288164]

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No. Sentence Comment
41 Missense mutations in ABCB6 can cause dominant familial pseudohyperkalemia (p.R375Q) [9] and ocular coloboma (p.A57T and L811V) [10]. Login to comment