ORPHA: 220493, 475; DO: 0110998;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q23.3 | Joubert syndrome 3 | 608629 | Autosomal recessive | 3 | AHI1 | 608894 |
A number sign (#) is used with this entry because of evidence that Joubert syndrome-3 (JBTS3) is caused by homozygous mutation in the AHI1 gene (608894) on chromosome 6q23.
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).
Lagier-Tourenne et al. (2004) described 2 consanguineous families with Joubert syndrome, one Turkish and the other of Swiss origin; the latter was originally described by Boltshauser and Isler (1977). There were 5 affected members in the Turkish family and 2 in the Swiss family. All patients had early hypotonia, molar tooth sign, and cerebellar vermis hypoplasia. Other clinical features included cognitive impairment, neonatal breathing problems, cerebellar ataxia, nystagmus, retinal dystrophy, reduced vision, kyphoscoliosis, and retarded skeletal growth.
In a review of patients with JBTS3, Valente et al. (2005) found that multiple central nervous system anomalies often occurred, including polymicrogyria, malformations of the corpus callosum, seizures, and spasticity. In contrast to patients with JBTS1, renal disease, liver disease, and polydactyly had not been reported.
Utsch et al. (2006) reported 2 Pakistani brothers, born of consanguineous parents, with JBTS3. Both boys had cerebellar ataxia, developmental delay, nystagmus, oculomotor apraxia. One developed end-stage renal failure by age 16 years due to nephronophthisis. Molecular analysis identified a homozygous mutation in the AHI1 gene (608894.0007). The findings indicated that renal involvement can occur in patients with JBTS3.
By linkage analysis, Lagier-Tourenne et al. (2004) identified a 13.1-cM interval spanning 8.2 Mb between markers D6S1620 and D6S1699 on chromosome 6q23 associated with Joubert syndrome. In the Turkish and Swiss families studied, the lod scores in favor of linkage at zero recombination were 4.1 and 2.3, respectively. Genotype-phenotype studies indicated that, unlike CORS2 (608091), JBTS3 appeared not to be associated with renal dysfunction.
The transmission pattern of Joubert syndrome-3 in the families reported by Dixon-Salazar et al. (2004) was consistent with autosomal recessive inheritance.
Ferland et al. (2004) identified a locus associated with Joubert syndrome on 6q23.2-q23.3 and found 3 deleterious mutations in the gene encoding Abelson helper integration site-1 (AHI1; 608894.0001-608894.0003). AHI1 was found to be most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicated that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.
In affected members of 3 consanguineous families with Joubert syndrome, some with cortical polymicrogyria, Dixon-Salazar et al. (2004) identified 1 missense and 2 frameshift mutations in the AHI1 gene.
Using a combination of haplotype analysis and gene sequencing, Parisi et al. (2006) screened 117 probands with Joubert syndrome for mutations in the AHI1 gene and identified a total of 15 novel and 5 previously identified mutations in 19 families, including nonsense, missense, splice site, and insertion mutations. Fourteen of the mutation-positive families were consanguineous, but no single founder mutation was apparent. In addition to the molar tooth sign, retinal dystrophy was present in 12 families; however, no individuals exhibited variable signs of Joubert syndrome such as polydactyly, encephalocele, colobomas, or liver fibrosis.
Valente et al. (2006) identified 15 different mutations (see, e.g., 608894.0004-608894.0006) in the AHI1 gene in 11 patients from 10 families with Joubert syndrome. These patients accounted for 7.3% of 137 probands with the molar tooth sign and Joubert-related disorders. A phenotype-specific group of Joubert syndrome plus retinopathy had an AHI1 mutation frequency was 21.7% (5 of 23 probands). Clinical analysis indicated that AHI1 mutations were not associated with kidney or liver changes. Retinal abnormalities ranged from retinitis pigmentosa to blindness. In 2 Egyptian patients with JBTS3 originally reported by Valente et al. (2006), Elsayed et al. (2015) found that the causative AHI1 mutation was a homozygous missense change (S761L; 608894.0011) rather than a C-terminal deletion (c.3263delGG; 608894.0004). The missense mutation was found by homozygosity mapping and whole-exome sequencing. Functional studies of the S761L variant were not performed, but structural modeling predicted that it would cause detrimental structural changes. Expression of the c.3263delGG mutation in zebrafish did not cause any abnormalities, suggesting that the C-terminal SH3 domain of AHI1 is not required for normal development.
By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a nonsense and a missense mutation in the AHI1 gene in affected members of 2 families with Joubert syndrome-3 (608894.0008 and 608894.0009, respectively).
Elsayed et al. (2015) determined that 2 variants in the AHI1 gene resulting in truncated proteins at the C terminus and lacking the SH3 domain (c.3263delGG, 608894.0004 and c.3196C-T) did not cause any abnormalities when expressed in zebrafish. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish. In addition, Elsayed et al. (2015) reported an unaffected member of a family segregating nonsyndromic hearing loss who carried the c.3196C-T variant in homozygosity. The findings indicated that the C-terminal SH3 domain of AHI1 is not required for normal development. Elsayed et al. (2015) noted the implications for assessing variants in AHI1 that are part of preconception screening panels, and emphasized that even truncating variants identified in known disease genes must undergo stringent functional and segregation analysis before being classified as pathogenic.
Boltshauser, E., Isler, W. Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropadiatrie 8: 57-66, 1977. [PubMed: 576733] [Full Text: https://doi.org/10.1055/s-0028-1091505]
Dixon-Salazar, T., Silhavy, J. L., Marsh, S. E., Louie, C. M., Scott, L. C., Gururaj, A., Al-Gazali, L., Al-Tawari, A. A., Kayserili, H., Sztriha, L., Gleeson, J. G. Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria. Am. J. Hum. Genet. 75: 979-987, 2004. [PubMed: 15467982] [Full Text: https://doi.org/10.1086/425985]
Elsayed, S. M., Phillips, J. B., Heller, R., Thoenes, M., Elsobky, E., Nurnberg, G., Nurnberg, P., Seland, S., Ebermann, I., Altmuller, J., Thiele, H., Toliat, M., and 9 others. Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe mendelian disease gene. Hum. Molec. Genet. 24: 2594-2603, 2015. [PubMed: 25616960] [Full Text: https://doi.org/10.1093/hmg/ddv022]
Ferland, R. J., Eyaid, W., Collura, R. V., Tully, L. D., Hill, R. S., Al-Nouri, D., Al-Rumayyan, A., Topcu, M., Gascon, G., Bodell, A., Shugart, Y. Y., Ruvolo, M., Walsh, C. A. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nature Genet. 36: 1008-1013, 2004. Note: Erratum: Nature Genet. 36: 1126 only, 2004. [PubMed: 15322546] [Full Text: https://doi.org/10.1038/ng1419]
Lagier-Tourenne, C., Boltshauser, E., Breivik, N., Gribaa, M., Betard, C., Barbot, C., Koenig, M. Homozygosity mapping of a third Joubert syndrome locus to 6q23. J. Med. Genet. 41: 273-277, 2004. [PubMed: 15060101] [Full Text: https://doi.org/10.1136/jmg.2003.014787]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Parisi, M. A., Doherty, D., Eckert, M. L., Shaw, D. W. W., Ozyurek, H., Aysun, S., Giray, O., Al Swaid, A., Al Shahwan, S., Dohayan, N., Bakhsh, E., Indridason, O. S., Dobyns, W. B., Bennett, C. L., Chance, P. F., Glass, I. A. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J. Med. Genet. 43: 334-339, 2006. [PubMed: 16155189] [Full Text: https://doi.org/10.1136/jmg.2005.036608]
Utsch, B., Sayer, J. A., Attanasio, M., Pereira, R. R., Eccles, M., Hennies, H.-C., Otto, E. A., Hildebrandt, F. Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome. Pediat. Nephrol. 21: 32-35, 2006. [PubMed: 16240161] [Full Text: https://doi.org/10.1007/s00467-005-2054-y]
Valente, E. M., Brancati, F., Silhavy, J. L., Castori, M., Marsh, S. E., Barrano, G., Bertini, E., Boltshauser, E., Zaki, M. S., Abdel-Aleem, A., Abdel-Salam, G. M. H., Bellacchio, E., and 12 others. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann. Neurol. 59: 527-534, 2006. [PubMed: 16453322] [Full Text: https://doi.org/10.1002/ana.20749]
Valente, E. M., Marsh, S. E., Castori, M., Dixon-Salazar, T., Bertini, E., Al-Gazali, L., Messer, J., Barbot, C., Woods, C. G., Boltshauser, E., Al-Tawari, A. A., Salpietro, C. D., Kayserili, H., Sztriha, L., Gribaa, M., Koenig, M., Dallapiccola, B., Gleeson, J. G. Distinguishing the four genetic causes of Joubert syndrome-related disorders. Ann. Neurol. 57: 513-519, 2005. Note: Erratum: Ann. Neurol. 57: 934 only, 2005. [PubMed: 15786477] [Full Text: https://doi.org/10.1002/ana.20422]