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

• Published in: American journal of human genetics 2012-07, Vol.91 (1), p.202-208
• Main Authors: Staropoli, John F., Karaa, Amel, Lim, Elaine T., Kirby, Andrew, Elbalalesy, Naser, Romansky, Stephen G., Leydiker, Karen B., Coppel, Scott H., Barone, Rosemary, Xin, Winnie, MacDonald, Marcy E., Abdenur, Jose E., Daly, Mark J., Sims, Katherine B., Cotman, Susan L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Child, Preschool; Deoxyribonucleic acid; DNA; Errors of metabolism; Female; Fundamental and applied biological sciences. Psychology; Genetic disorders; Genetics; Genetics of eukaryotes. Biological and molecular evolution; HEK293 Cells; Humans; Infant; Lipids (lysosomal enzyme disorders, storage diseases); Male; Medical genetics; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Mutation; Neurodegeneration; Neuronal Ceroid-Lipofuscinoses - genetics; Pedigree; Potassium Channels - genetics; Proteasome Endopeptidase Complex - genetics; Proteins; Ubiquitin - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2012.05.023

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.