PUBLICATION
Identification and Functional Analysis of a SLC33A1: c.339T>G (p.Ser113Arg) Variant in the Original SPG42 Family
- Authors
- Mao, F., Li, Z., Zhao, B., Lin, P., Liu, P., Zhai, M., Liu, Q., Shao, C., Sun, W., Gong, Y.
- ID
- ZDB-PUB-141118-1
- Date
- 2015
- Source
- Human Mutation 36(2): 240-9 (Journal)
- Registered Authors
- Keywords
- SLC33A1, exome sequencing, hereditary spastic paraplegias (HSP), mutation
- MeSH Terms
-
- Amino Acid Substitution
- Animals
- Bone Morphogenetic Proteins/physiology
- Genetic Association Studies
- Humans
- INDEL Mutation
- Membrane Transport Proteins/genetics*
- Polymorphism, Single Nucleotide
- Signal Transduction
- Spastic Paraplegia, Hereditary/genetics*
- Zebrafish
- PubMed
- 25402622 Full text @ Hum. Mutat.
Citation
Mao, F., Li, Z., Zhao, B., Lin, P., Liu, P., Zhai, M., Liu, Q., Shao, C., Sun, W., Gong, Y. (2015) Identification and Functional Analysis of a SLC33A1: c.339T>G (p.Ser113Arg) Variant in the Original SPG42 Family. Human Mutation. 36(2):240-9.
Abstract
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, co-segregated 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 co-injected 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. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping