Abstract

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 (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα 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.

Highlights

  • The neuronal ceroid lipofuscinosis (NCLs) are the most common group of inherited neurodegenerative diseases in children, with an incidence in the U.S of approximately 1 in 12,500 live births [1]

  • Independent replication studies are important especially in autosomal dominant neuronal ceroid lipofuscinosis (ANCL), wherein a critical evaluation of the literature led to the rejection of 68 cases published as Kufs’ disease [5], which means that there is a high rate of misdiagnosis in ANCLs. These results indicate that the genetic architecture of ANCL is more varied and complex than previously thought

  • After filtering for a minimum length good quality sequence of 30 and a minimal sequence read depth of 56, we identified on average 38,179684 coding single nucleotide substitutions (SNSs) at a transitions-to-transversions ratio of 3.05, and 2931610 small insertions and deletions, among all three individuals

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Summary

Introduction

The neuronal ceroid lipofuscinosis (NCLs) are the most common group of inherited neurodegenerative diseases in children, with an incidence in the U.S of approximately 1 in 12,500 live births [1]. Over the last fifteen years, at least 300 mutations in ten genes have been associated with NCLs such as CLN1 (PPT1 (MIM 256730)), CLN2 (TPP1 (MIM 204500)), CLN3 (MIM 204200), CLN5 (MIM 256731), CLN6 (MIM 601780), CLN7 (MFSD8 (MIM 610951)), CLN8 (MIM 600143), CLN10 (CTSD (MIM 610127)), CLCN6 (MIM 602726) and SGSH (MIM 605270) (NCL Mutation Database, URL). This genetic progress has led to the development of molecular testing tools and promising rational therapeutic approaches [3]. There is no cure for NCLs, and treatments are limited to palliative care

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