Rare exonic variant affects GRN splicing and contributes to frontotemporal lobar degeneration.

Heterozygous loss-of-function (LOF) mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. For most missense mutations, the contribution to FTLD is however unclear. We studied the pathogenicity of rare GRN missense mutations using patient biomaterials.

Genetic variants in progranulin upstream open reading frames increase downstream protein expression.

Premature termination codon (PTC) mutations in the granulin gene (GRN) lead to loss-of-function (LOF) of the progranulin protein (PGRN), causing frontotemporal lobar degeneration (FTLD) by haploinsufficiency. GRN expression is regulated at multiple levels, including the 5' untranslated region (UTR). The main 5' UTR of GRN and an alternative 5' UTR, contain upstream open reading frames (uORFs).

Uncovering the impact of noncoding variants in neurodegenerative brain diseases.

Neurodegenerative brain diseases (NBDs) are characterized by cognitive decline and movement impairments caused by neuronal loss in different brain regions. A large fraction of the genetic heritability of NBDs is not explained by the current known mutations. Genome-wide association studies identified novel disease-risk loci, adding to the genetic basis of NBDs.