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Case Reports
. 2012 Jul 13;91(1):202-8.
doi: 10.1016/j.ajhg.2012.05.023. Epub 2012 Jun 28.

A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system

John F Staropoli  1 , Amel Karaa, Elaine T Lim, Andrew Kirby, Naser Elbalalesy, Stephen G Romansky, Karen B Leydiker, Scott H Coppel, Rosemary Barone, Winnie Xin, Marcy E MacDonald, Jose E Abdenur, Mark J Daly, Katherine B Sims, Susan L Cotman
Affiliations
Case Reports

A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system

John F Staropoli et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Storage Material in a Molecularly Undefined Form of NCL (A) Electron micrographs demonstrating osmiophilic, membrane-bound storage material from peripheral blood (left panels) and a skin biopsy (right panels) from the proband. Arrows point to laminated inclusions, consistent with fingerprint profiles, in a lymphocyte. The upper right panel shows a fibroblast distended with a mixture of granular osmiophilic deposits (asterisk) and filamentous material, some of which is enclosed in vacuoles (arrowheads). The lower right panel shows a vacuole containing rectilinear profiles within the axon of a myelinated nerve. Scale bars represent 100 nm (lymphocyte), 500 nm (fibroblast), and 200 nm (nerve). (B) Early-passage (p ∗) in CLN3 and from an unaffected sibling heterozygous for the same CLN3 change. Lysates (∼30 μg) were probed for mitochondrial ATPase subunit c, the protein characteristically stored in NCL. GAPDH served as a loading control.
Figure 2
Figure 2
A Private KCTD7 Variant Identified by Whole-Exome Sequence Analysis of an Affected Sibling Pair and an Unaffected Sibling (A) A pedigree of the family shows similarly affected siblings (IV-1 and IV-2) that were ruled out for known forms of NCL by enzymatic and molecular testing. I-2 and I-3 are second cousins. Although no known consanguinity existed between the parents of the affected sibling pair, both sides of the family originate from neighboring villages in the state of Michoacán, Mexico. The green box indicates the sibling trio analyzed by whole-exome sequencing. (B) Sanger-sequence confirmation of the c.550C>T variant in exon 4 of KCTD7.
Figure 3
Figure 3
KCTD7 Is Abundant in Brain Tissue, and the NCL-Associated Variant Alters Its Subcellular Localization and Disrupts Its Interaction with Cullin-3 (A) The left panel shows protein lysates that were isolated from the indicated tissues from a wild-type 5-month-old C57BL/6J mouse and then subjected to SDS-PAGE and immunoblotting for KCTD7. Approximately 100 μg of protein were loaded per lane. Five micrograms of protein lysate from HEK 293T cells transfected with wild-type KCTD7 was loaded as a reference. In the right panel, 30 μg of protein from conditionally immortalized CbCln3+/+ or CbCln3Δex7/8/Δex7/8 murine cerebellar cell lysates was probed for KCTD7 and GAPDH. (B) Murine cerebellar cells (CbCln3+/+ cells) were transiently transfected with GFP alone (not shown) or with constructs encoding an N-terminal GFP fusion of wild-type or p.Arg184Cys KCTD7, and they were visualized by confocal microscopy. Arrows show sites of plasma-membrane localization. The scale bar represents 15 μm. (C) HEK 293T cells were transiently transfected with Myc-tagged cullin-3 (CUL3) or cullin-1 (CUL1) and untagged wild-type or p.Arg184Cys KCTD7. Lysates were immunoprecipitated with the Myc antibody and immunoblotted for KCTD7 or Myc. Lysates represent approximately 20% input. The asterisk indicates the immunoglobulin light chain.
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