| 1. |
- Ben Said, Mariem, et al.
(författare)
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Posterior microphthalmia and nanophthalmia in Tunisia caused by a founder c.1059_1066insC mutation of the PRSS56 gene
- 2013
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Ingår i: Gene. - : Elsevier. - 0378-1119 .- 1879-0038. ; 528:2, s. 288-294
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Tidskriftsartikel (refereegranskat)abstract
- Congenital microphthalmia (CMIC) is a common developmental ocular disorder characterized by a small, and sometimes malformed, eye. Posterior microphthalmia (PM) and nanophthalmia are two rare subtypes of isolated CMIC characterized by extreme hyperopia due to short axial length and elevated lens/eye volume ratio. While nanophthalmia is associated with a reduced size in both anterior and posterior segments, PM involves a normal-size anterior chamber but a small posterior segment. less thanbrgreater than less thanbrgreater thanSeveral genes encoding transcription and non-transcription regulators have been identified in different forms of CMIC. MFRP gene mutations have, for instance, been associated with nanophthalmia, and mutations in the recently identified PRSS56 gene have been linked to PM. So far, these two forms of CMIC have been associated with 9 mutations in PRSS56. Of particular interest, a c.1059_1066insC mutation has recently been reported in four Tunisian families with isolated PM and one Tunisian family with nanophthalmia. Here, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous Tunisian family (PM7) affected with PM and identified the same causative disease mutation. A total of 24 polymorphic markers spanning the PRSS56 gene in 6 families originating from different regions of Tunisia were analyzed to investigate the origin of the c.1059_1066insC mutation and to determine whether it arose in a common ancestor. A highly significant disease-associated haplotype, spanning across the 146 kb of the 2q37.1 chromosome, was conserved in those families, suggesting that c.1059_1066insC arose from a common founder. The age of the mutation in this haplotype was estimated to be around 1850 years. The identification of such founder effects may greatly simplify diagnostic genetic screening and lead to better prognostic counseling.
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| 2. |
- Hmani-Aifa, Mounira, et al.
(författare)
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A genome-wide linkage scan in Tunisian families identifies a novel locus for non-syndromic posterior microphthalmia to chromosome 2q37.1
- 2009
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Ingår i: HUMAN GENETICS. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 126:4, s. 575-587
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Tidskriftsartikel (refereegranskat)abstract
- Posterior microphthalmia (PM) is a relatively rare autosomal recessive condition with normal anterior segment and small posterior segment resulting in high hyperopia and retinal folding. It is an uncommon subtype of microphthalmia that has been mostly reported to coexist with several other ophthalmic conditions and to occur in sporadic cases. The membrane-type frizzled-related protein (MFRP) is the only gene so far reported implicated in autosomal recessive, non-syndromic and syndromic forms of PM. Here, we performed a clinical and genetic analysis using six consanguineous families ascertained from different regions of Tunisia and affected with non-syndromic PM that segregates as an autosomal recessive trait. To identify the disease-causing defect in these families, we first analysed MFRP gene, then some candidate genes (CHX10, OPA1, MITF, SOX2, CRYBB1-3 and CRYBA4) and loci (MCOP1, NNO1 and NNO2) previously implicated in different forms of microphthalmia. After exclusion of these genes and loci, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous pedigree. SNP genotyping revealed eight homozygous candidate regions on chromosomes 1, 2, 3, 6, 15, 17 and 21. Linkage analysis with additional microsatellite markers only retained the 2q37.1 region with a maximum LOD score of 8.85 obtained for D2S2344 at theta = 0.00. Further investigations are compatible for linkage of four more families to this region with a refined critical interval of 2.35 Mb. The screening of five candidate genes SAG, PDE6D, CHRND, CHRNG and IRK13 did not reveal any disease-causing mutation.
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| 3. |
- Hmani-Aifa, Mounira, et al.
(författare)
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Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family
- 2009
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Ingår i: EUROPEAN JOURNAL OF HUMAN GENETICS. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 17:4, s. 474-482
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p. Y6044C and p. W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23-24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.
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| 4. |
- Saidas Nair, K, et al.
(författare)
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Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice
- 2011
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Ingår i: NATURE GENETICS. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 43:6, s. 579-U118
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Tidskriftsartikel (refereegranskat)abstract
- Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people(1-3). Although 4 million people are bilaterally blind from ACG(4,5), the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure(6). Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG.
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