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Published on: July 30, 2014
Pelizaeus-Merzbacher-like disease caused by AIMP1/p43 homozygous mutation
Miora Feinstein1, Barak Markus, Iris Noyman
1National Institute of Biotechnology in the Negev, Beer Sheva, Israel.
Abstract:
Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by PLP1 mutations. A similar autosomal-recessive phenotype, Pelizaeus-Merzbacher-like disease (PMLD), has been shown to be caused by homozygous mutations in GJC2 or HSPD1. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD in which linkage to PLP1, GJC2, and HSPD1 was excluded. Through genome-wide homozygosity mapping and mutation analysis, we demonstrated in all affected individuals a homozygous frameshift mutation that fully abrogates the main active domain of AIMP1, encoding ARS-interacting multifunctional protein 1. The mutation fully segregates with the disease-associated phenotype and was not found in 250 Bedouin controls. Our findings are in line with the previously demonstrated inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.
Insights
A novel genetic cause for Pelizaeus-Merzbacher-like disease has been identified. A mutation in AIMP1 (ARS-interacting multifunctional protein 1) was found in a Bedouin kindred, highlighting its role in myelin development.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy linked to PLP1 mutations.
- Pelizaeus-Merzbacher-like disease (PMLD) presents similarly but is autosomal-recessive, typically caused by GJC2 or HSPD1 mutations.
Purpose of the Study:
- To identify the genetic cause of PMLD in a consanguineous Israeli Bedouin kindred.
- To investigate novel genetic factors contributing to hypomyelinating leukodystrophies.
Main Methods:
- Genome-wide homozygosity mapping was employed to identify shared regions of homozygosity in affected individuals.
- Mutation analysis, including sequencing, was performed to pinpoint the causative genetic variant.
- Segregation analysis and control population screening were conducted to validate the findings.
Main Results:
- Linkage to known PMLD genes (PLP1, GJC2, HSPD1) was excluded.
- A homozygous frameshift mutation in AIMP1 (ARS-interacting multifunctional protein 1) was identified in all affected individuals.
- This mutation abrogates the protein's main active domain and segregates with the disease phenotype, absent in controls.
Conclusions:
- Mutations in AIMP1 represent a novel genetic cause of Pelizaeus-Merzbacher-like disease.
- AIMP1 is crucial for maintaining axon integrity in the central and peripheral nervous system.
- This discovery expands the genetic landscape of hypomyelinating leukodystrophies.
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