Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy

Biswas, Susmito; Munier, Francis L.; Yardley, Jill; Hart-Holden, Niki; Perveen, Rahat; Cousin, Pascal; Sutphin, John E.; Noble, B A; Batterbury, Mark; Kielty, Cay M.; Hackett, Anna; Bonshek, Richard; Ridgway, A E A; McLeod, David; Sheffield, Val C.; Stone, Edwin M; Black, Graeme

doi:10.1093/hmg/10.21.2415

Cited by 346 publications

(320 citation statements)

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“…Moroi et al [2003] also indicated that PPCD in family UM:139 is unlikely to be the result of a mutation at the autosomal dominant congenital hereditary endothelial dystrophy locus (CHED1 [MIM121700]) located within and potentially allelic to the chromosome 20q PPCD locus [Toma et al, 1995], the autosomal recessive CHED2 locus (MIM217700) on chromosome 20p [Chan et al, 1982;Hand et al, 1999]. This paper also found that PPCD in this family is unlikely to be the result of mutations in the COL8A2 gene (MIM120252) on chromosome 1p [Biswas et al, 2001], which causes Fuchs endothelial corneal dystrophy (FECD) and has been given the alias PPCD2 by the Human Genome Nomenclature Committee because of the observation of a COL8A2 FECD mutation in two members of one PPCD family [Biswas et al, 2001]. In this study we provide significant evidence of a new PPCD locus, PPCD3, and discuss phenotypic variability within a single large family with PPCD.…”

Section: Introductionmentioning

confidence: 78%

“…Since the homeodomain transcription factor VSX1 has been implicated in PPCD [Heon et al, 2002], it is of interest to note that the PPCD3 critical interval contains the transcription factor, TCF8 (MIM189909), which has both homeodomain and zinc finger motifs [Williams et al, 1992;Funahashi et al, 1993;Franklin et al, 1994;Kent et al, 2002]. Although several collagen genes have been implicated in PPCD [Biswas et al, 2001] and in Alport syndrome, which can include PPCD [Colville and Savige, 1997;Kashtan, 1999], none of the known collagen genes are located in the interval between D10S213 and D10S578. Prioritization of candidate genes within this interval will call for additional bioinformatic analysis and evaluation of gene expression in relevant ocular tissues.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we excluded both the mapped PPCD locus on chromosome 20 [Heon et al, 2002] and the reported candidate PPCD gene on chromosome 1 [Biswas et al, 2001] as being responsible for PPCD in this family. Thus, the validity of this new PPCD locus is supported by: (1) significant evidence of linkage to markers in the vicinity of D10S1780, (2) a lack of evidence that the locus is elsewhere in the genome, and (3) evidence of exclusion of the other regions of the genome reportedly involved in PPCD.…”

Section: Discussionmentioning

confidence: 99%

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A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10

Shimizu

Krafchak

Fuse

et al. 2004

American J of Med Genetics Pt A

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Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant disorder characterized by corneal endothelial abnormalities, which can lead to blindness due to loss of corneal transparency and sometimes glaucoma. We mapped a new locus responsible for PPCD in a family in which we excluded the previously reported PPCD locus on 20q11, and the region containing COL8A2 on chromosome 1. Results of a 317-marker genome scan provided significant evidence of linkage of PPCD to markers on chromosome 10, with single-point LOD scores of 2.63, 1.63, and 3.19 for markers D10S208 (at θ = 0.03), D10S1780 (at θ = 0.00), and D10S578 (at θ = 0.06). A maximum multi-point LOD score of 4.35 was found at marker D10S1780. Affected family members shared a haplotype in an 8.55 cM critical interval that was bounded by markers D10S213 and D10S578. Our finding of another PPCD locus, PPCD3, on chromosome 10 indicates that PPCD is genetically heterogeneous. Guttae, a common corneal finding sometimes observed along with PPCD, were found among both affected and unaffected members of the proband's sib ship, but were absent in the younger generations of the family. Evaluation of phenotypic differences between family members sharing the same affected haplotype raises questions about whether differences in disease severity, including differences in response to surgical interventions, could be due to genetic background or other factors independent of the PPCD3 locus.

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Section: Introductionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10

Shimizu

Krafchak

Fuse

et al. 2004

American J of Med Genetics Pt A

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“…The disease is characterized by accumulation of extracellular collagenous deposits called "guttae" posterior to Descemet's membrane, the specialized extracellular matrix that backs the corneal endothelium [111]. Earlyonset FECD has been linked genetically to a mutation in the COL8A2 (2 chain of collagen VIII) gene encoding a component of Descemet's membrane [112]. Polymorphisms in the CLU gene have been associated with late-onset FECD [113,114].…”

Section: Corneal Dystrophies -This Is a Group Of Inherited Disorders mentioning

confidence: 99%

Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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, M. R. (2016). Clusterin in the eye: an old dog with new tricks at the ocular surface. Experimental Eye Research, Clusterin in the eye: an old dog with new tricks at the ocular surface AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease. Competing Interests: US patent 9,241,974 B2 entitled "Clusterin pharmaceuticals and treatment methods using the same" (inventors: MEF and SJ), assigned to the University of Southern California, is connected with this work. MEF holds a management position with Proteris Biotech, Inc., Pasadena, CA, which is developing Protearin for dry eye based on clusterin. MRW declares that he has no competing interests. Page 3 of 65 AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had bee...

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“…1 Endothelial cells from affected corneas demonstrate characteristics of epithelial cells including the ability to proliferate, leading to focal formation of multilayered areas, and multilamination of Descemet membrane. [2][3][4] PPCD is genetically heterogeneous with three identified loci; PPCD1 (OMIM #122000) on chromosome 20p with a currently undefined causative gene, [5][6][7] PPCD2 (OMIM #609140) associated with mutations in COL8A2, 8 and PPCD3 (OMIM #609141) caused by mutations in ZEB1. 9 To date, over 30 heterozygous nonsense and frameshifting mutations in ZEB1 have been identified.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

Lišková

Evans²,

Davidson³

et al. 2015

Eur J Hum Genet

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A substantial proportion of patients with posterior polymorphous corneal dystrophy (PPCD) lack a molecular diagnosis. We evaluated 14 unrelated probands who had a clinical diagnosis of PPCD who were previously determined to be negative for mutations in ZEB1 by direct sequencing. A combination of techniques was used including whole-exome sequencing (WES), single-nucleotide polymorphism (SNP) array copy number variation (CNV) analysis, quantitative real-time PCR, and long-range PCR. Segregation of potentially pathogenic changes with disease was confirmed, where possible, in family members. A putative run of homozygosity on chromosome 10 was identified by WES in a three-generation PPCD family, suggestive of a heterozygous deletion. SNP array genotyping followed by long-range PCR and direct sequencing to define the breakpoints confirmed the presence of a large deletion that encompassed multiple genes, including ZEB1. Identification of a heterozygous deletion spanning ZEB1 prompted us to further investigate potential CNVs at this locus in the remaining probands, leading to detection of two additional heterozygous ZEB1 gene deletions. This study demonstrates that ZEB1 mutations account for a larger proportion of PPCD than previously estimated, and supports the hypothesis that haploinsufficiency of ZEB1 is the underlying molecular mechanism of disease for PPCD3.

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Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy

Abstract: Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial

Cited by 346 publications

References 33 publications

A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10

A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10

Clusterin in the eye: An old dog with new tricks at the ocular surface

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

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