HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.

Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.

Objective: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. Methods: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. Results: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. Conclusion: PGRN mutations are not a common cause of ALS phenotypes.A myotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3-5 years from symptom onset. The pathogenic mechanism leading to motor neuron degeneration is unknown in the majority of cases. Frontotemporal dementia (FTD) is a degenerative disorder of the frontal and anterior temporal lobes.1 Clinical, pathological and genetic data suggest that ALS and FTD form a spectrum of disease.2 Approximately 5% of ALS patients have FTD (ALS-FTD) 3 and approximately half of patients with ''classical'' ALS have subtle frontal and temporal lobe cognitive impairment. 4 Many FTD cases similarly develop symptoms of motor neuron involvement during the course of their illness 5 and up to one third of FTD patients without overt motor symptoms have loss of anterior horn cells with characteristic ubiquitin inclusions in surviving motor neurons on autopsy. 6 Recently, mutations in the progranulin (PGRN) gene have been described as the cause of ubiquitin positive FTD. 7 8 The overlap between ALS and FTD prompted us to screen 272 cases of sporadic ALS, 40 familial ALS cases and 49 patients diagnosed with ALS-FTD for mutations in this gene. METHODS SubjectsGenetic studies were approved by local research ethics committees (NIA IRB protocol #2003-081). Diagnosis of ALS was based on the El Escorial diagnostic criteria.9 Samples used are outlined in table 1. The samples from the Coriell NINDS DNA repository consisted of 45 Caucasian women and 89 Caucasian men, with an average age of symptom onset of 54.3 years (range 26-81). Of these, 34 (25.4%) had bulbar onset disease, 98 (73.1%) had limb onset weakness and the remaining 2 (1.5%) cases presented with respiratory symptoms. Three sporadic ALS patients were reported to have cognitive changes, but did not have a formal diagnosis of FTD or dementia.Of the 48 Irish cases, 20 were women and 28 were men. Average age of symptom onset was 58.9 years (range 29-79). Eight (16.7%) patients initially manifested symptoms in bulbar musculature, 38 (79.2%) cases reported limb onset symptoms and the site of onset was unspecified in the remaining 2 (4.1%) cases.Samples obtained from the brain banks at Johns Hopkins University, Columbia University and the University of Miami, consisted of 26 women and 40 men (missing data = 15), with an average onset of 65.5 years...

We have recently described manufacturing of human induced pluripotent stem cells (iPSC) master cell banks (MCB) generated by a clinically compliant process using cord blood as a starting material (Baghbaderani et al. in Stem Cell Reports, 5(4), 647–659, 2015). In this manuscript, we describe the detailed characterization of the two iPSC clones generated using this process, including whole genome sequencing (WGS), microarray, and comparative genomic hybridization (aCGH) single nucleotide polymorphism (SNP) analysis. We compare their profiles with a proposed calibration material and with a reporter subclone and lines made by a similar process from different donors. We believe that iPSCs are likely to be used to make multiple clinical products. We further believe that the lines used as input material will be used at different sites and, given their immortal status, will be used for many years or even decades. Therefore, it will be important to develop assays to monitor the state of the cells and their drift in culture. We suggest that a detailed characterization of the initial status of the cells, a comparison with some calibration material and the development of reporter sublcones will help determine which set of tests will be most useful in monitoring the cells and establishing criteria for discarding a line.Electronic supplementary materialThe online version of this article (doi:10.1007/s12015-016-9662-8) contains supplementary material, which is available to authorized users.

Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Abeta plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.