Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UMLS:C0026827 (
hypotonia
)
5,860
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Spinocerebellar ataxia type 29 (SCA29) is autosomal dominant congenital ataxia characterized by early-onset motor delay,
hypotonia
, and gait ataxia. Recently, heterozygous missense mutations in an intracellular Ca
2+
channel, inositol 1,4,5-trisphosphate (IP
3
) receptor type 1 (IP
3
R1), were identified as a cause of SCA29. However, the functional impacts of these mutations remain largely unknown. Here, we determined the molecular mechanisms by which pathological mutations affect IP
3
R1 activity and Ca
2+
dynamics. Ca
2+
imaging using IP
3
R-null HeLa cells generated by genome editing revealed that all SCA29 mutations identified within or near the IP
3
-binding domain of IP
3
R1 completely abolished channel activity. Among these mutations, R241K, T267M, T267R, R269G, R269W, S277I, K279E, A280D, and E497K impaired IP
3
binding to IP
3
R1, whereas the T579I and N587D mutations disrupted channel activity without affecting IP
3
binding, suggesting that T579I and N587D compromise channel gating mechanisms.
Carbonic anhydrase-related protein
VIII (
CA8
) is an IP
3
R1-regulating protein abundantly expressed in cerebellar Purkinje cells and is a causative gene of congenital ataxia. The SCA29 mutation V1538M within the
CA8
-binding site of IP
3
R1 completely eliminated its interaction with
CA8
and
CA8
-mediated IP
3
R1 inhibition. Furthermore, pathological mutations in
CA8
decreased
CA8
-mediated suppression of IP
3
R1 by reducing protein stability and the interaction with IP
3
R1. These results demonstrated the mechanisms by which pathological mutations cause IP
3
R1 dysfunction, i.e., the disruption of IP
3
binding, IP
3
-mediated gating, and regulation via the IP
3
R-modulatory protein. The resulting aberrant Ca
2+
homeostasis may contribute to the pathogenesis of cerebellar ataxia.
...
PMID:Aberrant IP
3
receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29. 3042 31
