Heterozygous Loss-of-Function Variants in<i>CYP1B1</i>Predispose to Primary Open-Angle Glaucoma

Pasutto, Francesca; Chavarría-Soley, Gabriela; Mardin, Christian Y.; Michels-Rautenstrauss, Karin; Ingelman‐Sundberg, Magnus; Fernández-Martínez, Lorena T.; Weber, Bernhard H. F.; Rautenstrauß, Bernd; Reis, André

doi:10.1167/iovs.09-3880

Cited by 51 publications

(50 citation statements)

References 33 publications

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“…To date a digenic inheritance in open-angle glaucoma has been reported in patients with mutations in both MYOC and CYP1B1. 13,39 Thus, on the basis of present knowledge, it is likely that the POAG in patient ID99168 (Table 2) is mainly due to the presence of mutations p.Q368X in MYOC and p.N203S in CYP1B1, as these have been previously confirmed to have a pathological function. 13,40 In fact, according to our experimental results, the p.Q589H in RPGRIP1 seems to be non-pathological (Table 1 (Table 2) instead, the JOAG phenotype may be due mainly to the pathological p.T806I mutation in RPGRIP1 (Table 1) as the MYOC mutation, p.Q352K, has been previously reported to be a probable benign sequence change.…”

Section: Rpgrip1 and Primary Open Angle Glaucoma L Fernández-martínezmentioning

confidence: 73%

“…Further recruitment and clinical data have been previously reported. 13,14,19 All subjects were also screened for MYOC, OPTN (data not shown), WDR36, 19 CYP1B1 13 and NTF4 14 mutations (to note that patients with mutations in one of these candidate genes were also included in the present screening study as the etiology of glaucoma is still unknown).…”

Section: Study Populationmentioning

confidence: 99%

“…10 Altogether, mutations in these genes account for o10% of POAG cases. 11 In addition, association studies have implicated at least 20 other genes, 7,12 among them cytochrome P450-1B (CYP1B1) 13 and neurotrophin 4 (NTF4), 14 contributing to the pathogenesis of glaucoma, 7 but these are still insufficient to explain the most significant fraction of POAG cases. 15 This may not come as a surprise, as the POAG phenotype itself seems complex and to result from diverse pathological processes that involve, but are not limited to, the retina and optic nerve, the aqueous humor outflow pathways and even, as suggested recently, the cerebrospinal fluid dynamics.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

et al. 2011

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Section: Rpgrip1 and Primary Open Angle Glaucoma L Fernández-martínezmentioning

confidence: 73%

Section: Study Populationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

et al. 2011

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“…Enzymatic assays indicate c.1103G4A, p.(Arg368His) has markedly reduced activity while c.685G4A, p.(Glu229Lys) is a hypomorphic allele. 33,34 There was no evidence of glaucoma or Peters anomaly in Patient 9 (Family 9, II.1) or Patient 11 (Family 11, II.1). CYP1B1 can contribute to retinoic acid synthesis in embryonic development, 35 and retinoic Table 3 Other variants lacking appropriate segregation-allele frequencies in public databases, conservation and prediction categories acid receptor signalling regulates choroid fissure closure.…”

Section: Exome and Target Region Analysismentioning

confidence: 97%

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

et al. 2013

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Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/ microphthalmia.

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“…39 Our early observations of lack of clinical manifestations in CYP1B1/LTBP2 double carriers may be attributed to the involvement of the two genes in independent pathways of eye development and glaucoma pathogenesis. However, it is important to note that both CYP1B1 variantsp.E229K and p.R368H -lead to reduced, not abolished, enzyme activity and protein stability, 40,41 and display incomplete penetrance. 42,43 CYP1B1-LTBP2 interactions and their clinical implications need to be addressed in larger samples of double carriers of wellsupported pathogenic mutations.…”

Section: Population Genetics Of Pcg In Gypsiesmentioning

confidence: 99%

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

et al. 2010

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Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/ Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for B70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations -p.R299X/LTBP2 and p.E387K/CYP1B1.

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Heterozygous Loss-of-Function Variants inCYP1B1Predispose to Primary Open-Angle Glaucoma

Abstract: Heterozygous CYP1B1 mutations with absent or reduced relative enzymatic activity can be considered a risk factor for POAG.

Cited by 51 publications

References 33 publications

Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

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