期刊
HUMAN MUTATION
卷 36, 期 2, 页码 240-249出版社
WILEY
DOI: 10.1002/humu.22732
关键词
hereditary spastic paraplegias (HSP); exome sequencing; SLC33A1; mutation
资金
- Ministry of Science and Technology of China [2011CB966200]
- National Natural Science Foundation of China [31000653, 81321061, 81000548]
- Specialized Research Fund for the Doctoral Program of Higher Education of China [20100131120051]
- Scientific Research Foundation for Outstanding Young Scientist of Shandong Province [BS2012SW007]
Using whole-exome sequencing, we surveyed all the potential pathogenic variants in an SPG42 family and found five SNPs and four indels that are shared by two patients and lie in the mapped region. Two variants, SLC33A1 p.Ser113Arg and VEPH1 p.Gln433His, cosegregated with the disease. However, VEPH1 p.Gln433His was predicted to be tolerated, thus leaving SLC33A1 p.Ser113Arg as the most plausible causal variant in this family. We found that the phosphorylated SMAD1/5/8 (P-SMAD1/5/8) and BMP receptor type 1A (BMPR1A) were substantially upregulated in fibroblasts derived from an SPG42 individual. Slc33a1 knockdown zebrafish, which exhibited defects in morphology and axon outgrowth, also showed a significant elevation in the level of P-smad1/5/8. While the phenotypes in slc33a1 knockdown zebrafish could be rescued by human wild-type SLC33A1 mRNA, this rescuing effect was diminished by coinjected mutant mRNA encoding p.Ser113Arg, indicating that p.Ser113Arg variant acts in a dominant-negative manner. Importantly, pharmacological blockade of BMPR1 activity by dorsomorphin could efficiently rescue the phenotypic defects in slc33a1 knockdown zebrafish. These results indicate that SLC33A1 can negatively regulate BMP signaling.
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