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

Nature Genetics volume 36, pages 1008–1013 (2004)Cite this article

A Corrigendum to this article was published on 01 October 2004

Abstract

Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles1,2,3,4,5,6,7,8,9. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances5,6,7,8,10,11,12. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2–q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is 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 indicates 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.

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Figure 1: MRIs of a normal brain and of the brain of an individual with Joubert syndrome and mutations in AHI1.
Figure 2: The genotypes of two (of five) pedigrees with Joubert syndrome that defined the smallest region of homozygosity.
Figure 3: Linkage to JBTS3 and mutations in AHI1 in individuals with Joubert syndrome.
Figure 4: Spatial expression of mouse Ahi1 in brain during embryonic and postnatal development.
Figure 5: Phylogenetic tree showing AHI1 gene evolution in hominoids.

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Acknowledgements

We thank D. Reich, D. Pilbeam and members of the laboratory of C.A.W. for discussions; U. Berger and C. Patoine for help with the in situ hybridization studies; the Yerkes Regional Primate Research Center for primate tissues; and the families who participated in these studies. This work was supported by grants (to C.A.W.) from the National Institute of Neurological Disorders and Stroke, the March of Dimes, and the McKnight Foundation. C.A.W. is an Investigator of the Howard Hughes Medical Institute. R.J.F. is supported by a Young Investigator Award from Cure Autism Now. This work was also supported by a Mind/Brain/Behavior Interfaculty Initiative grant to M.R. and C.A.W. R.V.C. was supported by a Jacob K. Javits Graduate Fellowship.

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Author notes

  1. Russell J Ferland and Wafaa Eyaid: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Neurogenetics and Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, NRB 266, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Russell J Ferland, Laura D Tully, R Sean Hill, Adria Bodell & Christopher A Walsh

  2. Department of Pediatrics, King Fahad National Guard Hospital, Riyadh, 11426, Kingdom of Saudi Arabia

    Wafaa Eyaid & Doha Al-Nouri

  3. Department of Anthropology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Randall V Collura & Maryellen Ruvolo

  4. Department of Neurology, King Fahad National Guard Hospital, Riyadh, 11426, Kingdom of Saudi Arabia

    Ahmed Al-Rumayyan

  5. Department of Pediatrics, Hacettepe University Faculty of Medicine, Section of Child Neurology, Ankara, 06100, Turkey

    Meral Topcu

  6. Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Jeddah, 21499, Kingdom of Saudi Arabia

    Generoso Gascon

  7. Clinical Neurosciences & Pediatrics, Brown University School of Medicine, Providence, 02908, Rhode Island, USA

    Generoso Gascon

  8. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA

    Yin Yao Shugart

  9. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Christopher A Walsh

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Correspondence to Christopher A Walsh.

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Supplementary information

Supplementary Fig. 1

Genotypes of the three remaining pedigrees with Joubert Syndrome. (PDF 2 kb)

Supplementary Fig. 2

Mutations in AHI1 in patients with Joubert Syndrome. (PDF 149 kb)

Supplementary Fig. 3

Temporal expression of murine Ahi1 during brain development and post-natal development. (PDF 254 kb)

Supplementary Fig. 4

Schematic diagrams of the structure of mouse and human AHI1. (PDF 101 kb)

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Ferland, R., Eyaid, W., Collura, R. et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36, 1008–1013 (2004). https://doi.org/10.1038/ng1419

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