TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of α-dystroglycan and muscular dystrophy

Abstract

BackgroundTransport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation.Case presentationSubject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual.ConclusionRecessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.

TRAPPC11 functions in autophagy by recruiting ATG2B‐WIPI4/WDR45 to preautophagosomal membranes

“…A number of individuals with TRAPPC11 mutations have now been reported . Because the carboxy‐terminus of TRAPPC11 appears to be important for ATG2B‐WIPI4 recruitment to membranes (see Figures C and Table ), we examined the fibroblasts from one individual harboring the compound heterozygous mutations p.Ala372_Ser429del and p.Asp1127Valfs*47 in TRAPPC11 (note that a more detailed characterization of this individual will be reported elsewhere) to determine if this newly‐identified interaction was physiologically relevant.…”

“…Indeed, both defective autophagy and glycosylation have been implicated in muscular dystrophies, particularly those caused by improper glycosylation of the protein dystroglycan . Interestingly, one individual with a TRAPPC11 mutation was recently shown to have a dystroglycanopathy . Furthermore, the glycosyltransferases essential for some of the modifications on dystroglycan are Golgi‐resident enzymes that utilize the biosynthetic pathway to reach their destination .…”

“…These include lipid‐linked oligosaccharide synthesis for TRAPPC11 and chromosome congression for TRAPPC12 . In addition, both proteins have been implicated in human disease that manifests as muscular and neurodevelopmental phenotypes . Given the overall size of the TRAPP complexes, it is not unreasonable to expect their constituent proteins to have unique interacting partners, thereby allowing the complexes to coordinate distinct events even within a common pathway.…”

“…31,32 In addition, both proteins have been implicated in human disease that manifests as muscular and neurodevelopmental phenotypes. [33][34][35][36][37][38][39] Given the overall size of the TRAPP complexes, [40][41][42] it is not unreasonable to expect their constituent proteins to have unique interacting partners, thereby allowing the complexes to coordinate distinct events even within a common pathway. Thus, understanding the various roles that the TRAPP proteins play in cell physiology will shed light on the diseases caused by mutations in their genes.…”

A molecular overview of the primary dystroglycanopathies

“…20 As opposed to the constantly growing number of secondary and tertiary dystroglycanopathies so far identified, only a few cases of primary dystroglycanopathies have been found in human patients as well as in zebrafish. 20 As opposed to the constantly growing number of secondary and tertiary dystroglycanopathies so far identified, only a few cases of primary dystroglycanopathies have been found in human patients as well as in zebrafish.…”