Homozygosity Mapping in Families with Joubert Syndrome Identifies a Locus on Chromosome 9q34.3 and Evidence for Genetic Heterogeneity

Saar, Kathrin; Al‐Gazali, Lihadh; Sztriha, László; Rueschendorf, Franz; Nur-E-Kamal, Mohammed; Reis, André; Bayoumi, Riad

doi:10.1086/302655

Cited by 132 publications

(98 citation statements)

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“…Heterozygous deletion of CAC-NA1B may result in the reduction of N-type channel activity and can be a contributing factor for MR and/or epilepsy. An autosomal recessive neurological disorder, Joubert syndrome type 1 (JBTS1, OMIM #213300), was mapped close to D9S158 at 9q34.3 (Saar et al 1999). D9S158 was identified within RP11-83N9, which was deleted in three of our six cases.…”

Section: Resultsmentioning

confidence: 85%

A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

et al. 2004

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Patients with 9q34.3 terminal deletion usually show a clinically recognizable phenotype characterized by specific facial features (microcephaly, flat face, arched eyebrows, hypertelorism, short nose, anteverted nostrils, carp mouth and protruding tongue) in combination with severe mental retardation, hypotonia, and other anomalies. We analyzed six unrelated patients with a various 9q34.3 terminal deletion. While having different-sized 9q34.3 deletions, all of these patients shared several distinctive anomalies. These anomalies are likely to arise from a commonly deleted region at distal 9q34.3. Fluorescence in situ hybridization (FISH) analysis using a dozen BAC clones mapped at the 9q34.13-q34.3 region defined the shortest region of deletion overlap (SRO) as a 1-Mb segment proximal to 9qter containing eight known genes. Possible candidate genes delineating specific phenotypes of the 9q34.3 terminal deletion syndrome are discussed.

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Section: Resultsmentioning

confidence: 85%

A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

et al. 2004

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“…AHI1 is as a potential downstream effector of these pathways, as it is essential for commissural crossing in the corticospinal tract and SCPs and encodes a putative cytoplasmic phosphoprotein. Determining the signaling pathways by which AHI1 modulates cellular signals may help elucidate potential genes underlying the other two loci known to be associated with Joubert syndrome (JBTS1 and CORS2, also called JBTS2) [15][16][17] , as it is reasonable to speculate that such genes may be in the AHI1 pathway. Although we have no direct evidence, it seems that the Joubert syndrome phenotype, with its aberrant axonal patterns and associated motor abnormalities, combined with the molecular evolutionary pattern of selection and the evolutionary increase in the corticospinal tract of primates 25 , potentially implicates AHI1 in the evolution of some aspects of the distinctive motor programs that characterize humans.…”

Section: E T T E R Smentioning

confidence: 99%

Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome

et al. 2004

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“…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 .…”

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Distinguishing the four genetic causes of jouberts syndrome–related disorders

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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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Homozygosity Mapping in Families with Joubert Syndrome Identifies a Locus on Chromosome 9q34.3 and Evidence for Genetic Heterogeneity

Cited by 132 publications

References 18 publications

A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome

Distinguishing the four genetic causes of jouberts syndrome–related disorders

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