CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait.
We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.
Türkmen
Seval
S
Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Guo
Gao
G
Garshasbi
Masoud
M
Hoffmann
Katrin
K
Alshalah
Amjad J
AJ
Mischung
Claudia
C
Kuss
Andreas
A
Humphrey
Nicholas
N
Mundlos
Stefan
S
Robinson
Peter N
PN
D001259:Ataxia / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D002524:Cerebellar Ataxia / Q000151:congenital / Q000235:genetics / Q000503:physiopathology; D003241:Consanguinity; D017931:DNA Primers / Q000235:genetics; D004795:Enzyme Stability; D005260:Female; D020234:Gait Ataxia / Q000151:congenital / Q000235:genetics / Q000503:physiopathology; D020233:Gait Disorders, Neurologic / Q000235:genetics* / Q000503:physiopathology; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics*; D007493:Iraq; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D015398:Signal Transduction; D013577:Syndrome; D002256:Carbonic Anhydrases; D047908:Intracellular Signaling Peptides and Proteins
D014408:Biomarkers, Tumor; D017931:DNA Primers; D015544:Inositol 1,4,5-Trisphosphate; D053496:Inositol 1,4,5-Trisphosphate Receptors; C512818:CA8 protein, human; D002256:Carbonic Anhydrases; D047908:Intracellular Signaling Peptides and Proteins