Dataset Information

The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome.

ABSTRACT: Joubert syndrome (JS) is an autosomal recessive multisystem disease characterized by cerebellar vermis hypoplasia with prominent superior cerebellar peduncles (the "molar tooth sign" [MTS] on axial magnetic resonance imaging), mental retardation, hypotonia, irregular breathing pattern, and eye-movement abnormalities. Some individuals with JS have retinal dystrophy and/or progressive renal failure characterized by nephronophthisis (NPHP). Thus far, no mutations in the known NPHP genes, particularly the homozygous deletion of NPHP1 at 2q13, have been identified in subjects with JS. A cohort of 25 subjects with JS and either renal and/or retinal complications and 2 subjects with only juvenile NPHP were screened for mutations in the NPHP1 gene by standard methods. Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone. A control subject with NPHP and with a homozygous NPHP1 deletion was also identified, retrospectively, as having a mild MTS and borderline intelligence. The NPHP1 deletion represents the first molecular defect associated with JS in a subset of mildly affected subjects. Cerebellar malformations consistent with the MTS may be relatively common in patients with juvenile NPHP without classic symptoms of JS.

SUBMITTER: Parisi MA

PROVIDER: S-EPMC1182011 | biostudies-literature | 2004 Jul

REPOSITORIES: biostudies-literature

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The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome.

Parisi Melissa A MA Bennett Craig L CL Eckert Melissa L ML Dobyns William B WB Gleeson Joseph G JG Shaw Dennis W W DW McDonald Ruth R Eddy Allison A Chance Phillip F PF Glass Ian A IA

American journal of human genetics 20040511 1

Joubert syndrome (JS) is an autosomal recessive multisystem disease characterized by cerebellar vermis hypoplasia with prominent superior cerebellar peduncles (the "molar tooth sign" [MTS] on axial magnetic resonance imaging), mental retardation, hypotonia, irregular breathing pattern, and eye-movement abnormalities. Some individuals with JS have retinal dystrophy and/or progressive renal failure characterized by nephronophthisis (NPHP). Thus far, no mutations in the known NPHP genes, particular ...[more]

PMID: 15138899

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Project description:Joubert syndrome (JS) is a ciliopathy associated with mutations in numerous genes encoding cilia components. TALPID3 encoded by KIAA0856 in man (2700049A03Rik in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in KIAA0856 have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11-12 of Talpid3 in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. Talpid3 mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre-derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in Wnt7a expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of Talpid3. The Talpid3 conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for Talpid3 in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome.

Publications

The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome.

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