Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0700208 (scoliosis)
 8,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NGLY1-related disorder is a newly described autosomal recessive condition characterized by neurological, hepatic, ophthalmological findings and associated with dysmorphic features, constipation and scoliosis. It is caused by mutations in NGLY1, which encodes an enzyme, N-glycanase 1, involved in deglycosylation of glycoproteins, an essential step in the endoplasmic reticulum-associated degradation (ERAD) pathway. The disorder has been described in eight patients. We investigated the molecular basis and phenotype of NGLY1-related disorder in an additional patient. The proband is a 14-year-old who presented in early infancy with profound hypotonia and elevated transaminases. Liver biopsy showed lipid accumulation with dilated endoplasmic reticulum. He exhibited global developmental delay, acquired microcephaly, seizures, involuntary body movements, muscle atrophy, absent reflexes, and poor growth. He had multiple procedures for lacrimal duct stenosis and strabismus and had intractable blepharitis. He had severe osteopenia and persistent hypocholesterolemia. Whole exome sequencing revealed two novel variants in NGLY1: a truncating mutation, c.347C > G (p.S116X), and a splicing mutation, c.881 + 5G (p.IVS5 + 5G>T), predicted to abolish the splice donor site of exon 5. This study, along with previously reported cases, suggests that mutations in NGLY1 cause a recognizable phenotype and targeted sequencing should be considered in patients with typical presentation. This study expands the molecular spectrum of NGLY1-related condition and suggests that osteopenia and hypocholesterolemia may be part of the phenotype.
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PMID:Multi-systemic involvement in NGLY1-related disorder caused by two novel mutations. 2570 56

N-glycanase 1 (NGLY1) deficiency, an autosomal recessive disease caused by mutations in the NGLY1 gene, is characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, movement disorders and other neurological phenotypes. Because of few animal models that recapitulate these clinical signatures, the mechanisms of the onset of the disease and its progression are poorly understood, and the development of therapies is hindered. In this study, we generated the systemic Ngly1-deficient rodent model, Ngly1-/- rats, which showed developmental delay, movement disorder, somatosensory impairment and scoliosis. These phenotypes in Ngly1-/- rats are consistent with symptoms in human patients. In accordance with the pivotal role played by NGLY1 in endoplasmic reticulum-associated degradation processes, cleaving N-glycans from misfolded glycoproteins in the cytosol before they can be degraded by the proteasome, loss of Ngly1 led to accumulation of cytoplasmic ubiquitinated proteins, a marker of misfolded proteins in the neurons of the central nervous system of Ngly1-/- rats. Histological analysis identified prominent pathological abnormalities, including necrotic lesions, mineralization, intra- and extracellular eosinophilic bodies, astrogliosis, microgliosis and significant loss of mature neurons in the thalamic lateral and the medial parts of the ventral posterior nucleus and ventral lateral nucleus of Ngly1-/- rats. Axonal degradation in the sciatic nerves was also observed, as in human subjects. Ngly1-/- rats, which mimic the symptoms of human patients, will be a useful animal model for preclinical testing of therapeutic options and understanding the detailed mechanisms of NGLY1 deficiency.
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PMID:Ngly1 -/- rats develop neurodegenerative phenotypes and pathological abnormalities in their peripheral and central nervous systems. 3225 58