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A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System  John F. Staropoli, Amel Karaa, Elaine T. Lim,

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Presentation on theme: "A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System  John F. Staropoli, Amel Karaa, Elaine T. Lim,"— Presentation transcript:

1 A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System  John F. Staropoli, 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  The American Journal of Human Genetics  Volume 91, Issue 1, Pages (July 2012) DOI: /j.ajhg Copyright © 2012 The American Society of Human Genetics Terms and Conditions

2 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 < 3) lymphoblastoid cell lines were established from an affected and unaffected sibling in the family studied here, as well as from a JNCL subject homozygous for a nonsense change (p.Tyr199∗) 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. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

3 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. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

4 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 CbCln3 Δex7/8/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. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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