Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage

Abstract

We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.

Figure 1

Family Pedigree and Clinical Features of NCL in Proband (A) Pedigree of family (arrow indicates proband) indicating mutation status for GRN (c.813_816del). Plasma progranulin values are shown in red (ng/ml; median normal value is 126 ng/ml). (B) Retinal photograph of proband showing optic atrophy, arteriolar attenuation, and irregular retinal pigmentation. (C) Electron micrograph of skin biopsy from the proband. Typical fingerprint profiles within a membrane-bound structure in an eccrine pale cell are shown. The bar indicates 100 nm.

Figure 2

Results of Linkage Analysis Autosomal genome-wide LOD scores, adjusted for inbreeding, for the family under a fully penetrant recessive genetic model.

Figure 3

NCL Pathology in Progranulin-Deficient Mice Electron micrograph showing a high-power view of one of the storage granules in a neuron from the habenula of a Grn^−/− mouse. The pattern corresponds to the rectilinear complex, which, along with fingerprint profiles, is characteristic of most types of NCL. The arrow points to a pentalaminar profile. The bar indicates 100 nm.