. Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability. Cell Rep. 2018 Jun 5;23(10):2844-2851. PubMed.


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  1. Heterozygous loss-of-function mutations in the progranulin gene (GRN) cause FTD pointing toward haploinsufficiency as the underlying disease mechanism. Most mutations are nonsense mutations, causing efficient nonsense-mediated RNA decay of the mutant allele and a reduction of ~50 percent of GRN expression. However, for some missense mutations a clear segregation in FTD pedigrees has been shown, and whether these mutations also cause haploinsufficiency is less straightforward.

    Some missense mutations in the coding region may affect the secretion or proteolytic processing of progranulin into granulins (Wang et al., 2010; Kleinberger et al., 2016) or induce missorting of the protein (Shankaran et al., 2008). Missense mutations located in the signal peptide were shown to reduce secretion of progranulin (Shankaran et al., 2008; Mukherjee et al., 2008). Here, Pinarbarsi and colleagues study the mechanism of pathogenic missense mutations in the signal peptide. The A9D and W7R mutations disrupt the hydrophobic domain of the signal peptide and reduce binding to SRP, which is required to initiate transfer to the ER as first step of secretion. Interestingly, the failure to recruit SRP during initial translation also triggers a recently discovered protein quality-control pathway RAPP (or regulation of aberrant protein production) with degradation of the corresponding transcript and thus reduced protein levels. This study reveals important mechanistic insight in how mutations in the signal peptide can induce haploinsufficiency. In addition, it opens avenues for intervention: Strategies that enhance the binding of SRP to A9D or W7R mutant protein, thereby forcing the nascent protein to the ER and preventing the occurrence of RAPP, could potentially correct the detrimental effects of such mutations and could restore normal GRN levels.


    . Pathogenic cysteine mutations affect progranulin function and production of mature granulins. J Neurochem. 2010 Mar;112(5):1305-15. PubMed.

    . Reduced secretion and altered proteolytic processing caused by missense mutations in progranulin. Neurobiol Aging. 2016 Mar;39:220.e17-26. Epub 2015 Dec 29 PubMed.

    . Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion. J Biol Chem. 2008 Jan 18;283(3):1744-53. Epub 2007 Nov 5 PubMed.

    . Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat. 2008 Apr;29(4):512-21. PubMed.

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