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Jansen J.C.,Radboud University Nijmegen | Cirak S.,Institute For Humangenetik | Van Scherpenzeel M.,Radboud University Nijmegen | Van Scherpenzeel M.,Donders Institute for Brain | And 41 more authors.
American Journal of Human Genetics | Year: 2016

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma. © 2016 by The American Society of Human Genetics. All rights reserved.


PubMed | University Hospital Freiburg, Institute for Medical Genetics, Institute For Humangenetik, Osaka Medical Center and Research Institute for Maternal and Child Health and 14 more.
Type: Journal Article | Journal: American journal of human genetics | Year: 2016

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.


Schmidt-Hieber M.,Oncology and Transfusion Medicine | Blau I.W.,Oncology and Transfusion Medicine | Richter G.,Oncology and Transfusion Medicine | Turkmen S.,Institute for Medical Genetics | And 7 more authors.
Cancer Genetics and Cytogenetics | Year: 2010

We analyzed karyotype stability in 22 patients with acute leukemia at relapse or disease progression after allogeneic stem cell transplantation (allo-SCT). Karyotypes before and at relapse after allo-SCT were different in 15 patients (68%), the most frequent type being clonal evolution either alone or combined with clonal devolution (13 patients). Patients with and without a karyotype change did not differ significantly in overall survival (OS) (median, 399 vs. 452 days; P = 0.889) and survival after relapse (median, 120 vs. 370 days; P = 0.923). However, acquisition of additional structural chromosome 1 abnormalities at relapse after allo-SCT occurred more frequently than expected and was associated with reduced OS (median, 125 vs. 478 days; P = 0.008) and shorter survival after relapse (median, 37 vs. 370 days; P = 0.002). We identified a previously undescribed clonal evolution involving t(15;17) without PML-RARA rearrangement in an AML patient. We conclude that a karyotype change is common at relapse after allo-SCT in acute leukemia patients. Moreover, our data suggest that additional structural chromosome 1 abnormalities are overrepresented at relapse after allo-SCT in these patients and, in contrast to a karyotype change per se, are associated with reduced OS and shorter survival after relapse. © 2010 Elsevier Inc.


Leushacke M.,Max Planck Institute for Molecular Genetics | Leushacke M.,Free University of Berlin | Sporle R.,Max Planck Institute for Molecular Genetics | Bernemann C.,Max Planck Institute for Molecular Genetics | And 10 more authors.
PLoS ONE | Year: 2011

In tumor cells, stepwise oncogenic deregulation of signaling cascades induces alterations of cellular morphology and promotes the acquisition of malignant traits. Here, we identified a set of 21 genes, including FGF9, as determinants of tumor cell morphology by an RNA interference phenotypic screen in SW480 colon cancer cells. Using a panel of small molecular inhibitors, we subsequently established phenotypic effects, downstream signaling cascades, and associated gene expression signatures of FGF receptor signals. We found that inhibition of FGF signals induces epithelial cell adhesion and loss of motility in colon cancer cells. These effects are mediated via the mitogen-activated protein kinase (MAPK) and Rho GTPase cascades. In agreement with these findings, inhibition of the MEK1/2 or JNK cascades, but not of the PI3K-AKT signaling axis also induced epithelial cell morphology. Finally, we found that expression of FGF9 was strong in a subset of advanced colon cancers, and overexpression negatively correlated with patients' survival. Our functional and expression analyses suggest that FGF receptor signals can contribute to colon cancer progression. © 2011 Leushacke et al.

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