A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System

Abstract

Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14.

The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina

“…This makes difficult accurate candidate gene selection for direct sequencing [7]. Furthermore, it is estimated that ~8% of individuals diagnosed with NCL, by conservative clinical and histopathological criteria, have been ruled out for mutations in the known NCL-associated genes, suggesting that additional NCL genes remain unidentified [8].…”

“…The DNA screening was done under a research protocol [5,6]. This methodology has emerged in recent years as a useful tool for NCL diagnosis and enhancing subtype classification [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Increasing recognition of variant phenotypes associated with specific NCL genetic etiologies challenges diagnosis based solely on clinical history or pathologic features.…”

A Short Commentary of Neuronal Ceroid Lipofuscinoses; Phenotypes in Congenital to Preschooler

“…Electron microscopy studies of lymphocytes show lysosomal storage material of fingerprint-like proteins (FP) and GRODs. Only an infantile form has been reported [14].…”

“…The age of onset is usually 8 to 24 months; patients initially present with intractable seizures, followed by myoclonic movement, progressive motor deterioraton, and with or without intracellular inclusions. Visual loss also occurs [14].Causal gene is located at 7q11 (CLN14/KCTD7). The CLN14 causes changes in function of the potassium channel tetramerization domain-containing protein 7 (KCTD7), which is present in the cytoplasm and peripherally associated with cellular membranes.…”

Neuronal ceroid-lipofuscinoses

“…CLN11 arises from mutations in the progranulin gene GRN, which is also associated with frontotemporal lobar degeneration [37]. CLN14, a rare infantile NCL, results from mutations in KCTD7 that encodes the potassium channel tetramerization domain-containing protein 7, which is related to the ubiquitin-proteasome system [38].…”