AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome

2.50
Hdl Handle:
http://hdl.handle.net/2336/6496
Title:
AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome
Authors:
Parisi, M A; Doherty, D; Eckert, M L; Shaw, D W W; Ozyurek, H; Aysun, S; Giray, O; Al Swaid, A; Al Shahwan, S; Dohayan, N; Bakhsh, E; Indridason, O S; Dobyns, W B; Bennett, C L; Chance, P F; Glass, I A
Citation:
J. Med. Genet. 2006, 43(4):334-9
Issue Date:
1-Apr-2006
Abstract:
BACKGROUND: Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1). METHODS: We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis. RESULTS: We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions. CONCLUSIONS: Overall, 11% of subjects had AHI1 mutations, while approximately 2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype-phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://jmg.bmj.com/cgi/content/abstract/43/4/334

Full metadata record

DC FieldValue Language
dc.contributor.authorParisi, M A-
dc.contributor.authorDoherty, D-
dc.contributor.authorEckert, M L-
dc.contributor.authorShaw, D W W-
dc.contributor.authorOzyurek, H-
dc.contributor.authorAysun, S-
dc.contributor.authorGiray, O-
dc.contributor.authorAl Swaid, A-
dc.contributor.authorAl Shahwan, S-
dc.contributor.authorDohayan, N-
dc.contributor.authorBakhsh, E-
dc.contributor.authorIndridason, O S-
dc.contributor.authorDobyns, W B-
dc.contributor.authorBennett, C L-
dc.contributor.authorChance, P F-
dc.contributor.authorGlass, I A-
dc.date.accessioned2006-12-11T16:40:54Z-
dc.date.available2006-12-11T16:40:54Z-
dc.date.issued2006-04-01-
dc.date.submitted2006-12-11-
dc.identifier.citationJ. Med. Genet. 2006, 43(4):334-9en
dc.identifier.issn1468-6244-
dc.identifier.pmid16155189-
dc.identifier.doi10.1136/jmg.2005.036608-
dc.identifier.otherNEP12-
dc.identifier.urihttp://hdl.handle.net/2336/6496-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractBACKGROUND: Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1). METHODS: We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis. RESULTS: We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions. CONCLUSIONS: Overall, 11% of subjects had AHI1 mutations, while approximately 2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype-phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.en
dc.language.isoenen
dc.publisherBritish Medical Associationen
dc.relation.urlhttp://jmg.bmj.com/cgi/content/abstract/43/4/334en
dc.subject.meshAbnormalities, Multipleen
dc.subject.meshAdaptor Proteins, Signal Transducingen
dc.subject.meshAmino Acid Motifsen
dc.subject.meshBrain Stemen
dc.subject.meshCerebellumen
dc.subject.meshCohort Studiesen
dc.subject.meshFemaleen
dc.subject.meshKidney Diseases, Cysticen
dc.subject.meshMaleen
dc.subject.meshMutationen
dc.subject.meshPedigreeen
dc.subject.meshProteinsen
dc.subject.meshResearch Support, N.I.H., Extramuralen
dc.subject.meshRetinal Degenerationen
dc.subject.meshSyndromeen
dc.titleAHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndromeen
dc.typeArticleen
dc.format.digYES-

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