Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms

Abstract

Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

“…Our findings also provide insight into the function of PGRN. Recently, a potential role of PGRN in lysosome homeostasis has emerged based on the discovery that multiple cases of homozygous GRN mutation carriers develop neuronal ceroid lipofuscinosis-11 (CNL11), a lysosomal storage disease [4,18,50,105]. We, and other labs, have found that PGRN is trafficked to the lysosome and processed by cathepsins into granulins, which may be bioactive [47,68,133].…”

Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin‐deficient mice

“…Recent studies have suggested novel functions of PGRN in lysosomes. Complete loss of PGRN leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease (Smith et al, 2012;Almeida et al, 2016;Huin et al, 2020). Although primary trafficking pathways of PGRN are not completely clear, cell biologic studies demonstrated that PGRN can be either sorted intracellularly from ER/Golgi or taken up extracellularly and targeted to lysosomes through sortilin (Hu et al, 2010) and prosaposin (Zhou et al, 2015) pathways, where it undergoes proteolytic processing into stable granulin peptides (Holler et al, 2017;Lee et al, 2017;Zhou et al, 2017b).…”

Lysosomal Diseases and Neuropsychiatry: Opportunities to Rebalance the Mind

“…In other neurodegenerative diseases, there is the strong association of heterozygous variants of PGN, the progranulin gene with fronto-temporal dementia and variants of GNPTAB, GNPTG, and the functionally related NAGPA gene with non-syndromic stuttering. Since homozygous or biallelic mutations of PGN are responsible respectively for neuronal ceroid lipofuscinosis type 11 and for the mucolipidosis subtypes, characterized by multiple lysosomal effects, dose effects of heterozygous gene variants in causation of diverse neuropsychiatric diseases is clearly established (Huin et al, 2020;Raza et al, 2016). The extent to which such rare variants directly account for mental illness is emerging from population-wide whole-genome sequencing data -a promising approach in national health initiatives to improve diagnosis (Walkley et al, 2010).…”