Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

Choi, Alex; Lao, Richard; Tang, Paul Ling-Fung; Wan, Eunice; Wasima, Mayer; Bardakjian, Tanya; Shaw, Gary M.; Kwok, Pui‐Yan; Schneider, Adele; Slavotinek, Anne

doi:10.1038/ejhg.2014.119

Cited by 47 publications

(32 citation statements)

References 34 publications

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“…The 2 siblings with microphthalmia (IV‐1 and IV‐3) were sequenced and a novel homozygous missense mutation in the PXDN gene was identified (c.3211A>G [p.Arg1071Gly], Table ). Mutations in PXDN have been shown to cause anterior segment anomalies of the eye in at least two reports, one of which describes 2 siblings with microphthalmia in addition to anterior segment dysgenesis . Further analysis of the exome data uncovered a homozygous novel frameshift deletion in the NIPAL4 gene in IV‐1, which causes congenital ichthyosis, type 6 (c.1310_1317del [p.Leu437Glnfs*35], Table ) .…”

Section: Resultsmentioning

confidence: 99%

“…Mutations in PXDN have been shown to cause anterior segment anomalies of the eye in at least two reports, one of which describes 2 siblings with microphthalmia in addition to anterior segment dysgenesis. 22,23 Further analysis of the exome data uncovered a homozygous novel frameshift deletion in the NIPAL4 gene in IV-1, which causes congenital ichthyosis, type 6 (c.1310_1317del [p.Leu437Glnfs*35], Table 1). 24 Sanger sequencing confirmed segregation for both variants.…”

Section: Patients With Multiple Genetic Diseases In This Studymentioning

confidence: 99%

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Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing

et al. 2017

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Section: Resultsmentioning

confidence: 99%

Section: Patients With Multiple Genetic Diseases In This Studymentioning

confidence: 99%

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing

et al. 2017

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“…Furthermore, multiple additional extracellular matrix proteins and their modifying enzymes also contribute to ASD in mice and patients, including FBN2, 47 LAMB2, 48 heparin sulfate proteoglycans COL18, 49 AGRN, 50 and heparan sulfate synthesize enzymes. 50,51 Perhaps the most relevant is the recent identification that mutations in peroxidasin, a key enzyme in extracellular organization of COL4A1 and COL4A2, cause congenital cataracts, ASD and developmental glaucoma in patients 52,53 and in mice. 54 The extents to which the pathogenic mechanisms involved in these cases are distinct or overlapping need to be explored.…”

Section: Discussionmentioning

confidence: 99%

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Mao¹,

Smith

Alavi³

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Mao M, Smith RS, Alavi MV, et al. Strain-dependent anterior segment dysgenesis and progression to glaucoma in Col4a1 mutant mice. Invest Ophthalmol Vis Sci. 2015;56:6823-6831. DOI:10.1167/iovs.15-17527 PURPOSE. Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma.METHODS. Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves.RESULTS. We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.CONCLUSIONS. Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.

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“…В настоящее время выделяют 8 клинико-генетических типов собственно дисгенезий переднего отрезка глаза, ассоциированных с мутациями в различных генах [51,52]. К этой группе также можно отнести и другие состояния, вызываемые мутациями в тех же генах: врожденная аниридия (OMIM #106210), аномалии группы синдрома Аксенфельда-Ригера (OMIM #602482), иридогониодисгенезии I, II типа (OMIM #601631 и OMIM #137600), аномалия Петерса (OMIM #604229) и некоторые другие [53] (табл.…”

Section: изолированная врожденная аниридия ассоциированная с другимиunclassified

Genetic Approaches to Differential Diagnosis of Hereditary Forms of Congenital Aniridia

Vasilyeva¹,

Алексеевна²,

Voskresenskaya

et al. 2017

Annals RAMS

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Congenital aniridia (AN) is a hereditary autosomal dominant developmental disorder of the eye. Heterozygous mutations in the PAX6 gene and chromosomal rearrangements involving the 11p13 locus lie behind the pathogenesis of the AN. The key role of the PAX6 gene in the regulation of embryogenesis and the pleiotropic effect of this transcription factor explain the damage of several tissues of the anterior and posterior segments of the eye, brain structures, and the disturbance of morphogenesis and endocrine function of the pancreas observed in AN. Recently AN has been considered a syndromic pathology by several researchers. The review suggests classification and summarizes information on the clinical characteristics and genetic basis of various forms of AN. The problem of discrimination of clinical-genetic variants of the dysgenesis of the anterior segment of the eye and the differential diagnosis of PAX6-associated AN with WAGR syndrome, anterior dysgenesis, other rare monogenic and chromosomal syndromes is discussed, and the role of molecular diagnostics is emphasized.

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Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

Cited by 47 publications

References 34 publications

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Genetic Approaches to Differential Diagnosis of Hereditary Forms of Congenital Aniridia

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