ABSTRACT
BACKGROUND: Transport 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 PRESENTATION: Subject 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. CONCLUSION: Recessive 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.
Subject(s)
Dystroglycans/metabolism , Muscular Dystrophies/genetics , Mutation , Qb-SNARE Proteins/genetics , Vesicular Transport Proteins/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Brain/diagnostic imaging , Diffusion Magnetic Resonance Imaging/methods , Female , Glycosylation , Humans , Infant , Muscle, Skeletal/metabolism , Muscular Dystrophies/congenital , Muscular Dystrophies/diagnostic imaging , Muscular Dystrophies/metabolismABSTRACT
Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the ß isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.
Subject(s)
Cell Adhesion Molecules, Neuronal/genetics , Exons/genetics , Gene Deletion , Genotype , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Nerve Tissue Proteins/genetics , Phenotype , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Adolescent , Adult , Calcium-Binding Proteins , Child , Child Development Disorders, Pervasive/diagnosis , Child Development Disorders, Pervasive/genetics , DNA Copy Number Variations , Female , Humans , Infant , Introns , Male , Microarray Analysis , Muscle Hypotonia/congenital , Muscle Hypotonia/diagnosis , Muscle Hypotonia/genetics , Neural Cell Adhesion Molecules , Protein Isoforms/geneticsSubject(s)
Abnormalities, Multiple/diagnosis , Developmental Disabilities/diagnosis , Face/abnormalities , Fingers/abnormalities , Kidney Neoplasms/diagnosis , Toes/abnormalities , Wilms Tumor/diagnosis , Aortic Valve/abnormalities , Child , Child, Preschool , Female , Heart Defects, Congenital/diagnosis , Heart Septal Defects, Atrial/diagnosis , Heart Septal Defects, Ventricular/diagnosis , Humans , Infant , Intellectual Disability/diagnosis , Kidney Neoplasms/surgery , Male , Microcephaly/diagnosis , Seizures/congenital , Seizures/drug therapy , Siblings , Wilms Tumor/surgeryABSTRACT
A distinguishing characteristic of high performance organizations is a strong internal control structure-controls that ensure patient care, compliance with regulations, internal efficiencies, and financial reporting. It is controls on financial reporting that are receiving a great deal of attention under a new law, the Sarbanes-Oxley Act of 2002. Public companies are now required by law to document controls over financial reporting, in order to fully address exposures and the effectiveness of current controls. Though many healthcare organizations are not directly affected by the law, regulatory agencies could follow suit and require similar compliance. In fact, several states have introduced bills that require nonprofit organizations to adhere to portions of the act. This article provides a guide for organizations desiring to stay ahead of the curve.
