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The mevalonate kinase deficiency (MKD) is an inherited disorder of the cholesterol biosynthesis. This early-onset disease is caused by mutations in the MVK gene and belongs to the ultra-rare diseases. Patients are divided into two groups, the mevalonate kinase deficiency (MKD)/ hyperimmunoglobulinemia D syndrome (HIDS) group and the mevalonic aciduria (MVA) group, which is the more severe end of the spectrum of symptoms. The clinical picture includes recurrent febrile crises, often accompanied by hepatosplenomegaly, lymphadenopathy, mental retardation, ocular symptoms, psychomotor retardation, skin rashes, cardiomyopathy, hypotonia and facial dysmorphism. The new patient MVK9 displayed the typical symptoms of MVA patients and was initially diagnosed by the elevated mevalonate acid excretion in urine, which is the gold standard screening method for diagnosis. The patient died at day 11 due to cardiac arrest. Genetic analysis confirmed the MVK deficiency by identifying the homozygous mutation c.803T>C in exon 9 leading to amino acid change p.Ile268Thr. To get a better understanding of the pathophysiologic mechanism of the MVK deficiency, ten more MVK patients were included in this work. Sanger sequencing of these patients revealed two new mutations, c.782T>C in MVK10 and c.790dupC in MVK3, which are not in the NCBI ClinVar database yet. All 11 patients belong to the MVA group, whereby also differences in the severity of the phenotype were present. MVK expression analysis revealed a diminished MVK protein expression in all MVK patients. Biochemical and genetic analyses used in this study comprised western blots, immunofluorescence studies, lectin blots, N-glycan analysis, nCounter expression analysis, qRT-PCR, lipid analysis and metabolite measurements. Based on the results of this work it could be demonstrated for the first time that a MVK defect leads to a global N-glycosylation deficiency in patients caused by low levels of dolichol and dolichyl phosphate. In addition, hints to an impact on O-mannosylation and C-mannosylation have been found. The MVK defect therefore belongs to the disease group of congenital disorders of glycosylation (CDG), and it is proposed to name this new defect `MVK-CDG´. |
