<i>AHI1</i> gene mutations cause specific forms of Joubert syndrome–related disorders

Valente, Enza Maria; Brancati, Francesco; Silhavy, Jennifer L.; Castori, Marco; Marsh, Sarah Arnaud; Barrano, Giuseppe; Bertini, Enrico; Boltshauser, Eugen; Zaki, Maha S.; Abdel-Aleem, Alice; Abdel-Salam, Ghada M H; Bellacchio, Emanuele; Battini, Roberta; Cruse, Robert P.; Dobyns, William B.; Krishnamoorthy, Kalpathy S.; Lagier‐Tourenne, Clotilde; Magee, Alex; Pascual-Castroviejo, I; Salpietro, Carmelo; Sarco, Dean; Dallapiccola, Bruno; Gleeson, Joseph G.

doi:10.1002/ana.20749

Cited by 127 publications

(144 citation statements)

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“…However, it must be noted that age of examination of some patients was too young to safely exclude the development of a progressive renal disease such as NPH. The INPP5E phenotypic spectrum appears to largely overlap with that related to AHI1 mutations; 18 conversely, none of the INPP5E-mutated patients presented polydactyly or encephalocele, two features that are often associated with mutations in genes also causative of MKS, such as TMEM216, CEP290, TMEM67 or RPGRIP1L. 5,[19][20][21] In one patient with pure JS (COR28), only a single heterozygous INPP5E mutation could be detected, despite complete sequencing of the coding regions and canonical splice sites, and search for genomic rearrangements.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

et al. 2013

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Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

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Section: Discussionmentioning

confidence: 99%

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

et al. 2013

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“…Notably, truncating mutations are found to be the most frequent types (80%) that abolish completely or, in part, the two critical domains (WD40 and SH3) of AHI-1. 47 Therefore, it is reasonable to speculate that the truncated forms of AHI-1 generated by point mutations, or altered splice variants, are critical in the development of certain diseases, such as SS. Future experiments are in progress to fully understand the molecular mechanism, biological function and clinical value of deregulated AHI-1 expression involving in the SS development.…”

Section: Discussionmentioning

confidence: 99%

Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas

et al. 2006

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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 .…”

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confidence: 99%

Distinguishing the four genetic causes of jouberts syndrome–related disorders

Valente

Marsh

Castori

et al. 2005

Annals of Neurology

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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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AHI1 gene mutations cause specific forms of Joubert syndrome–related disorders

Cited by 127 publications

References 19 publications

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas

Distinguishing the four genetic causes of jouberts syndrome–related disorders

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