Description, Nomenclature, and Mapping of a Novel Cerebello-Renal Syndrome with the Molar Tooth Malformation

Valente, Enza Maria; Salpietro, D. C.; Brancati, Francesco; Bertini, Enrico; Galluccio, Tiziana; Tortorella, Gaetano; Briuglia, Silvana; Dallapiccola, Bruno

doi:10.1086/378241

Cited by 90 publications

(81 citation statements)

References 24 publications

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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.…”

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confidence: 99%

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

et al. 2004

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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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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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“…In patients with JS, three genetic loci have been mapped until recently to 9q34.3 (JBTS1: OMIM213300), to 11p12-q13.3 (JBTS2: OMIM608091), and to 6q23 (JBTS3: OMIM608629) (5)(6)(7)(8). Of these, JBTS3 is the only locus with which a diseasespecific gene has been identified, AHI1 (9,10).…”

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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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Description, Nomenclature, and Mapping of a Novel Cerebello-Renal Syndrome with the Molar Tooth Malformation

Cited by 90 publications

References 24 publications

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

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

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