Dataset Information

Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD.

ABSTRACT:

Objective

To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD).

Methods

Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing.

Results

We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype.

Conclusions

A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms.

SUBMITTER: van der Zee J

PROVIDER: S-EPMC5027801 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD.

van der Zee Julie J Mariën Peter P Crols Roeland R Van Mossevelde Sara S Dillen Lubina L Perrone Federica F Engelborghs Sebastiaan S Verhoeven Jo J D'aes Tine T Ceuterick-De Groote Chantal C Sieben Anne A Versijpt Jan J Cras Patrick P Martin Jean-Jacques JJ Van Broeckhoven Christine C

Neurology. Genetics 20160916 5

<h4>Objective</h4>To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD).<h4>Methods</h4>Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing.<h4>Results</h4>We identifie ...[more]

PMID: 27668283

Similar Datasets

Project description:We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSP?). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSP?. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSP?. We found that these mutations dramatically decrease the affinity of CSP? for the membrane. We did not identify any significant effect on palmitoylation status of CSP?. However, a reduction of CSP? membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSP? has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.

Dataset Information

Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD.

Objective

Methods

Results

Conclusions

Publications

Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets