A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis.
نویسندگان
چکیده
Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.
منابع مشابه
Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy.
Choline kinase is the first step enzyme for phosphatidylcholine (PC) de novo biosynthesis. Loss of choline kinase activity in muscle causes rostrocaudal muscular dystrophy (rmd) in mouse and congenital muscular dystrophy in human, characterized by distinct mitochondrial morphological abnormalities. We performed biochemical and pathological analyses on skeletal muscle mitochondria from rmd mice....
متن کامل[New congenital muscular dystrophy due to CHKB mutations].
Congenital muscular dystrophy with mitochondrial structural abnormalities (MIM #602541), or also called megaconial congenital muscular dystrophy, is characterized clinically by early-onset muscle wasting and severe mental retardation, and pathologically by peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy. Based up...
متن کاملProtein glycosylation in disease: new insights into the congenital muscular dystrophies.
Glycosylation is the most frequent modification of proteins and is important for many ligand-receptor interactions. Recently, defects in protein glycosylation have been linked to several forms of congenital muscular dystrophy that are frequently associated with brain abnormalities. Muscle-eye-brain disease and Walker-Warburg syndrome are caused by mutations in enzymes involved in O-mannosylatio...
متن کاملANTICALMODULIN DRUGS DUE TO THE NET EFFECTS CANNOT ANTAGONIZE DIBUTYRYL-CAMP-MEDIATED SUPPRESSION OF DE NOVO SYNTHESIZED LIPID SECRETION IN BOTH CULTURED MCARDLE CELLS AND RAT HEPATOCYTES
The effects and interaction between cAMP-analogue dibutyryl-cAMP and calmodulin antagonists were investigated on de novo synthesis and secretion of lipids in cultures of hepatoma McArdle-RH7777 cells and normal rat hepatocytes. Dibutyryl cAMP caused a significant decrease in the secretion of de novo synthesized triacyl [3H] glycerol in both cultures of McArdle cells and rat hepatocytes. The ...
متن کاملANTICALMODULIN DRUGS DUE TO THE NET EFFECTS CANNOT ANTAGONIZE DIBUTYRYL-CAMP-MEDIATED SUPPRESSION OF DE NOVO SYNTHESIZED LIPID SECRETION IN BOTH CULTURED MCARDLE CELLS AND RAT HEPATOCYTES
The effects and interaction between cAMP-analogue dibutyryl-cAMP and calmodulin antagonists were investigated on de novo synthesis and secretion of lipids in cultures of hepatoma McArdle-RH7777 cells and normal rat hepatocytes. Dibutyryl cAMP caused a significant decrease in the secretion of de novo synthesized triacyl [3H] glycerol in both cultures of McArdle cells and rat hepatocytes. The ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- American journal of human genetics
دوره 88 6 شماره
صفحات -
تاریخ انتشار 2011