Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.
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 peduncles. 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 disturbances. 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.
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, Massachusetts 02115, USA.
Russell J
RJ
Ferland
Wafaa
W
Eyaid
Randall V
RV
Collura
Laura D
LD
Tully
R Sean
RS
Hill
Doha
D
Al-Nouri
Ahmed
A
Al-Rumayyan
Meral
M
Topcu
Generoso
G
Gascon
Adria
A
Bodell
Yin Yao
YY
Shugart
Maryellen
M
Ruvolo
Christopher A
CA
Walsh
D000015:Abnormalities, Multiple / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D001933:Brain Stem / Q000002:abnormalities; D002531:Cerebellum / Q000002:abnormalities*; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010802:Phylogeny; D013577:Syndrome
C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D009419:Nerve Tissue Proteins