A Congenital Muscular Dystrophy with Mitochondrial Structural Abnormalities Caused by Defective De Novo Phosphatidylcholine Biosynthesis

Abstract

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.

Phosphatidylcholine Affects the Role of the Sorting and Assembly Machinery in the Biogenesis of Mitochondrial β-Barrel Proteins

“…In the present study we show that PC is specifically required for the functions of the SAM complex in the biogenesis of mitochondrial ␤-barrel proteins and the assembly of the TOM complex. This observation may have important implications for pathological developments like non-alcoholic steatohepatitis and congenital muscular dystrophy, which were found in tissues defective in PC synthesis (78,79).…”

“…In humans, defects in the synthesis of PC were found in patients suffering from congenital muscular dystrophy (79). Interestingly, the patient cells contained mitochondria with abnormal morphology, pointing to a role of PC in mitochondrial biogenesis (79). However, it was unclear whether PC may also be required for the function of specific membrane-integrated proteins.…”

“…Mice deficient in PE methyltransferase developed non-alcoholic steatohepatitis when fed with choline-deficient diet (78). In humans, defects in the synthesis of PC were found in patients suffering from congenital muscular dystrophy (79). Interestingly, the patient cells contained mitochondria with abnormal morphology, pointing to a role of PC in mitochondrial biogenesis (79).…”

Choline Kinase β Mutant Mice Exhibit Reduced Phosphocholine, Elevated Osteoclast Activity, and Low Bone Mass

“…A recent study has established that the forelimb deformity in CHKB-deficient mice is due to altered growth plate physiology in the embryo, implicating a role for CHKB in endochondral bone formation (42). Homozygous and compound heterozygous mutations in CHKB have been identified in patients with congenital muscular dystrophy (17)(18)(19)43).…”

“…Deletion of Chka is embryonically lethal in mice attesting to its fundamental role in embryonic development (15), whereas loss of Chkb results in severe rostrocaudal muscular dystrophy in skeletal muscle and bone deformity at the forelimb (16). Recent studies have identified a subset of human muscular dystrophy patients with CHKB mutations (17)(18)(19).…”