CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.

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.

Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications.

BACKGROUND AND AIMS: Liver cirrhosis represents an advanced stage of hepatic fibrosis characterized by distortion of organ architecture and formation of regenerative nodules. Retrospective series reported percutaneous liver biopsy to miss cirrhosis in about 30%. The aim of this study was to prospectively compare diagnostic sensitivity regarding the detection of cirrhosis and the complication rates of percutaneous versus minilaparoscopic liver biopsy in chronic liver disease. METHODS: Eight hundred fifty-seven patients were randomized to percutaneous (415) or to minilaparoscopic liver biopsy (442). Macroscopic liver evaluation was documented as normal, fibrosis, or cirrhosis. Liver specimens were assessed blindly according to the modified Ishak score. RESULTS: Demographic and clinical data of procedure groups were comparable. Histologic grading alone diagnosed cirrhosis in 22.3% (n=85) of liver specimens obtained by percutaneous route compared with 26.0% (n=98) obtained by minilaparoscopy (P=0.270). By combining macroscopy and histology, minilaparoscopic staging diagnosed a significantly higher rate of liver cirrhoses with 33.8% (n=127) compared with percutaneous route with 22.3% (n=85) (P=0.001). Analysis of minilaparoscopic data revealed that 33 of the 128 cirrhoses were diagnosed by inspection only, suggesting a 26% underestimation of cirrhosis by histology alone. Severe complications occurred in 1.0% (n=4) of percutaneous and in 0.2% (n=1) of minilaparoscopic procedures (P=0.025). CONCLUSIONS: Minilaparoscopic evaluation based upon the combined macroscopic and histologic assessment is more sensitive with regards to the detection of cirrhosis and has a comparable safety profile.