Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome

Utsch, Boris; Sayer, John A.; Attanasio, Massimo; Pereira, Rob Rodrigues; Eccles, Michael R.; Hennies, Hans Christian; Hildebrandt, Friedhelm

doi:10.1007/s00467-005-2054-y

Cited by 88 publications

(62 citation statements)

References 18 publications

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“…On the surface, the association between ARL13B and JS is consistent with the hypothesis that Joubert syndrome and related disorders (JSRD) are ciliopathy disorders, or diseases caused by ciliary defects (Bielas et al, 2009;Cantagrel et al, 2008;Castori et al, 2005;Dixon-Salazar et al, 2004;Gleeson et al, 2004;Gorden et al, 2008;Harris, 2007;Helou et al, 2007;Jacoby et al, 2009;Sharma et al, 2008;Utsch et al, 2006;Wolf et al, 2007). However, phenotypical analysis of patients with ARL13B mutations and sequence analysis of the ARL13B gene in patients with non-classical forms of JS seem to suggest that mutations in ARL13B are restricted to the classical form of JS, with symptoms predominantly limited to brain structure and function (Cantagrel et al, 2008).…”

Section: Introductionsupporting

confidence: 77%

Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

2009

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arl13b was initially cloned as the novel cystic kidney gene scorpion (sco) in zebrafish and was shown to be required for cilia formation in the kidney duct. In mouse, a null mutant of Arl13b shows abnormal ultrastructure of the cilium and defective sonic hedgehog (Shh) signaling. Importantly, a recent study linked mutations in ARL13B to a classical form of Joubert syndrome (JS), an autosomal recessive disorder characterized by a distinctive cerebellar malformation. In this study, we analyzed the zebrafish arl13b (sco) mutant and gene products in detail. We first demonstrate that Arl13b is a protein that is highly enriched in the cilium and is required for cilia formation in multiple organs in zebrafish, and that knockdown of arl13b leads to multiple cilia-associated phenotypes. We additionally show that multiple regions of Arl13b are required for its localization to the cilium. By means of rescuing experiments with a series of deletion and point mutants, we further demonstrate that the ciliary localization is crucial for the in vivo function of Arl13b. Together, these results strongly support the hypothesis that JS-related disease (JSRD) is a ciliopathy, or a disease caused by ciliary defects, and that Arl13b functions mainly through the cilium.

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Section: Introductionsupporting

confidence: 77%

Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

2009

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“…Mutations in the AHI1 gene (chromosome 6q23, MIM[*608894]) account for about 10% of patients with the MTS and lead to a prevalent phenotype of JS plus retinal abnormalities, with the kidneys usually spared [14][15][16] . Homozygous deletions of NPHP1 (chromosome 2q13, MIM[*607100]), which represent the most frequent cause of juvenile isolated nephronophthisis, have been described only in four JSRD patients with invariable renal involvement and occasional retinopathy 10,17 .…”

Section: Introductory Paragraphmentioning

confidence: 99%

Distinguishing the four genetic causes of jouberts syndrome–related disorders

Valente

Marsh

Castori

et al. 2005

Annals of Neurology

100

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Joubert syndrome is a severe developmental disorder mainly consisting of ataxia, oculomotor apraxia and mental retardation and characterized by cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the "molar tooth sign" 1,2 . Patients frequently display additional features of cystic kidney disease progressing to renal failure and ocular manifestations including retinopathy, encompassing the Joubert Syndrome Related Disorders (JSRD) group of conditions [3][4][5] . We used homozygosity mapping to identify a novel locus on chromosome 12 and subsequently truncating mutations in the centrosomal protein 290 (CEP290) gene in four families and a missense mutation in a fifth family. These families display pleiotropic forms of JSRD with variable retinal and renal manifestations. CEP290 expression was detected in developing murine tissues, most notably in proliferating cerebellar granule neuron populations, and showed centrosome and cilia intracellular localization in non-neuronal cells. Our data imply a direct connection between JSRDs and other cilia/centrosomal human disorders such as isolated nephronophthisis, Senior-Loken, Bardet-Biedl and Meckel syndromes 6,7 . 4 Joubert syndrome (JS) is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia and breathing abnormalities in the neonatal period 1 . Neuroradiologically, JS is characterized by a peculiar malformation of the midbrain-hindbrain junction known as the "molar tooth sign" (MTS), consisting of cerebellar vermis hypo/aplasia, thick and mal-oriented superior cerebellar peduncles and abnormally deep interpeduncular fossa 2 . The MTS has subsequently been reported in a group of syndromes termed "Joubert Syndrome Related Disorders" (JSRDs), displaying the neurological features of JS associated with involvement of other organs such as the eye and kidney (mainly retinal dystrophy and nephronophthisis). Additional clinical features include optic coloboma, polydactyly, liver fibrosis and other central nervous system malformations 3-4 . At least eight distinct syndromes sharing the MTS have been described so far. However, their nosologic delineation is still problematic due to the wide phenotypic variability both within and among families 5 . Genetic heterogeneity mirrors clinical heterogeneity of JSRDs, with two genes (AHI1/JBTS3 and NPHP1/JBTS4) and two additional genetic loci (JBTS1 and JBTS2) identified so far [8][9][10][11][12][13] . has been detected in six families characterized by multiorgan involvement and 5 striking phenotypic variability 18 . In our series, eighteen consanguineous JSRD families did not show linkage to any of the known loci, supporting further genetic heterogeneity. In the largest family (COR27), a simulation study performed with the program SLINK revealed a maximum expected LOD score of 3.60, indicating that this family was informative to detect linkage. A 10-cM resolution genome-wide screen identified a marker on chromosome 12q (D12S1064) that generated a LOD score of...

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“…Of these, JBTS3 is the only locus with which a diseasespecific gene has been identified, AHI1 (9,10). The phenotype that is linked to JBTS1 and JBTS3 loci was initially found to be restricted to neurologic and retinal involvement (11); however, more recently, AHI1 mutations have also been detected in patients with both JS and nephronophthisis (12,13). JBTS2 was also associated with renal and hepatic abnormalities (6,7).…”

mentioning

confidence: 99%

High NPHP1 and NPHP6 Mutation Rate in Patients with Joubert Syndrome and Nephronophthisis

Tory¹,

Lacoste²,

Bürglen³

et al. 2007

Journal of the American Society of Nephrology

151

156

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Joubert syndrome (JS) is an autosomal recessive disorder that is described in patients with cerebellar ataxia, mental retardation, hypotonia, and neonatal respiratory dysregulation. Kidney involvement (nephronophthisis or cystic renal dysplasia) is associated with JS in one fourth of known cases. Mutations in three genes-AHI1, NPHP1, and NPHP6-have been identified in patients with JS. However, because NPHP1 mutations usually cause isolated nephronophthisis, the factors that predispose to the development of neurologic involvement are poorly understood. In an attempt to identify such genetic determinants, a cohort of 28 families with nephronophthisis and at least one JS-related neurologic symptom were screened for mutations in AHI1, NPHP1, and NPHP6 genes. NPHP1 and NPHP6 homozygous or compound heterozygous mutations were found in 13 (46%) and six (21%) unrelated patients, respectively. Two of the 13 patients with NPHP1 mutations carried either a heterozygous truncating mutation in NPHP6 or a heterozygous missense mutation in AHI1. Furthermore, five patients with NPHP1 mutations carried the AHI1 variant R830W, which was predicted to be "possibly damaging" and was found with significantly higher frequency than in healthy control subjects and in patients with NPHP1 mutations without neurologic symptoms (five of 26 versus four of 276 and three of 152 alleles; P < 0.001 and P < 0.002, respectively). In contrast to the variable neurologic and milder retinal phenotype of patients with NPHP1 mutations, patients with NPHP6 mutations presented with a more severe neurologic and retinal phenotype. In conclusion, NPHP1 and NPHP6 are major genes of nephronophthisis associated with JS. Epistatic effects that are provided by heterozygous NPHP6 and AHI1 mutations and variants may contribute to the appearance of extrarenal symptoms in patients with NPHP1 mutations.

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Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome

Cited by 88 publications

References 18 publications

Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

Distinguishing the four genetic causes of jouberts syndrome–related disorders

High NPHP1 and NPHP6 Mutation Rate in Patients with Joubert Syndrome and Nephronophthisis

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