Identification and characterization of genes and mutations in the ALS-FTD continuum
13 November 2017
UAntwerp, Campus Drie Eiken, Building Q? Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
Phuoc Hung Nguyen
Christine Van Broeckhoven, Julie van der Zee
PhD defence Phuoc Hung Nguyen - Department of Biomedical Sciences
Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease predominantly affecting the upper and lower motor neurons. Up to 15% of ALS patients are clinically diagnosed with frontotemporal dementia (FTD). FTD is an early onset dementia, characterized by disturbances in behavior, personality, and language, resulting from the degeneration of the frontal and temporal lobes. ALS and FTD share mutual pathological and genetic features, and they are now considered two components of one disease continuum, referred to as the ALS-FTD spectrum. FTD has a high genetic heritability, and mutations in known causal genes explain about 40% of patients compared to 68% in ALS, implying that considerably more genes have not been pinpointed yet.
In this presented research, we performed extended mutation screens and phenotypic profiling of three novel genes in the ALS-FTD continuum, the coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), tubulin alpha 4a (TUBA4A), and NIMA-related kinase 1 (NEK1) genes, to investigate the genetic contribution of these genes to ALS-FTD in the Belgian population. In CHCHD10, we detected a novel nonsense mutation in a patient with atypical clinical FTD and pathology-confirmed Parkinson’s disease (PD), raising a potential link between CHCHD10 and PD. Transcription analysis showed that the resulting mRNA was degraded by nonsense-mediated mRNA decay. In TUBA4A, two novel mutations were identified, including a frameshift mutation leading to a truncated protein in a pure FTD patient and a missense mutation in two sibs with familial ALS harboring C9orf72 repeat expansion and NEK1 loss-of-function (LOF) mutations. In line with previous findings, we identified NEK1 LOF mutations in ~1% ALS patients versus 0.16% control individuals. Interestingly, the frequency of oligogenic carriers (carriers with more than one mutated gene) in the NEK1 positive group was significantly higher than what would be expected by chance, and therefore, supporting the concept of an oligogenic inheritance model in ALS, where NEK1 variants could modify disease presentation of driving mutations.
Exome sequencing in an unresolved Portuguese FTD family with peri-rolandic atrophy led to the identification of a double missense mutation in the matrix metalloproteinase 13 (MMP13) gene, that co-segregated with the disease within the family and was also present in an unrelated Portuguese FTD patient. Haplotype sharing analysis showed that all the mutation carriers shared about 1.7Mb on chromosome 11. Follow-up screening of MMP13 in unrelated Portuguese, Spanish and Belgian ALS-FTD replication cohorts revealed a significant enrichment of rare variants in patients compared to controls, as well as a second double mutation in a Belgian FTD patient. First line functional experiments were suggestive for reduced secretion and enhanced collagenase activity for the double mutants. Although promising, this research needs further investigation to provide supportive evidence for a true causal implication of MMP13 in FTD. If successful, this may expand the relevance of MMPs and MMP-based treatments to FTD.