Disorders of the inhibitory glycine receptor: the spastic mouse

The mutant mouse spastic suffers from a motor disorder of autosomal recessive inheritance which is characterized by tremor, myoclonic episodes, and a disturbed righting response. The most prominent alteration in the mutant is a substantial deficit of postsynaptic glycine receptor channels resulting in a dramatic reduction of glycinergic synaptic inhibition. Function and structure of the glycine receptor protein appear unaffected, which argues for a regulatory rather than a structural effect of the spastic mutation. It appears that other alterations in the spastic mouse are secondary to this fundamental disturbance in the balance of excitatory and inhibitory impulses. In particular, a significant increase in GABAA receptors of the lower parts of the CNS may serve a compensatory function, counteracting in part losses of glycinergic inhibition. Pharmacological experiments indeed show that facilitation of GABAA receptor-mediated inhibition alleviates symptoms of the spastic motor disorder. The recent cDNA cloning of glycine receptor subunits should help define the molecular mechanism by which the spastic gene causes the glycine receptor deficit.     

Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes

Hermansky-Pudlak syndrome (HPS) has evolved into a group of genetically distinct disorders characterized by oculocutaneous albinism, a storage pool deficiency, and impaired formation or trafficking of intracellular vesicles. HPS-1 results from mutations in the HPS1 gene and affects approximately 400 individuals in northwest Puerto Rico due to a 16-bp duplication in exon 15. Another 13 mutations have been reported in non-Puerto Ricans. HPS1 codes for a 79.3 kDa cytoplasmic protein of unknown function. HPS-1 patients typically develop fatal pulmonary fibrosis in their fourth decade. HPS-2 is caused by mutations in ADTB3A, which codes for the beta3A subunit of the adaptor protein-3 complex, AP3. This coat protein complex has been localized to the TGN as well as to a peripheral endosomal compartment. Evidence indicates that AP3 plays a role in the stepwise process of vesicular trafficking which leads to formation of the melanosomal, platelet dense body and lysosomal compartments. All three known HPS-2 patients had childhood neutropenia and infections. HPS-3 results from mutations in HPS3 and affects central Puerto Ricans homozygous for a 3904-bp deletion removing exon 1. At least 8 non-Puerto Rican patients have other HPS3 mutations, including an IVS5+1G->A splicing mutation in five Ashkenazi Jewish patients. HPS3 codes for a 113.7 kDa protein of unknown function. HPS-3 manifests with mild hypopigmentation and bleeding. All types of HPS are diagnosed by whole mount electron microscopic demonstration of absent platelet dense bodies, and molecular diagnoses are available for the Puerto Rican HPS1 and HPS3 founder mutations. Mouse and Drosophila models provide candidates for new genes causing HPS in humans. These genes will reveal the pathways by which specialized vesicles of lysosomal lineage arise within cells.     

Lipodystrophies: Disorders of adipose tissue biology

The adipocytes synthesize and store triglycerides as lipid droplets surrounded by various proteins and phospholipids at its surface. Recently, the molecular basis of some of the genetic syndromes of lipodystrophies has been elucidated and some of these genetic loci have been found to contribute to lipid droplet formation in adipocytes. The two main types of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL). So far, three CGL loci: 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli–Seip Congenital Lipodystrophy 2 (BSCL2) and caveolin 1 (CAV1) and four FPL loci: lamin A/C (LMNA), peroxisome proliferator-activated receptor γ (PPARG), v-AKT murine thymoma oncogene homolog 2 (AKT2) and zinc metalloprotease (ZMPSTE24), have been identified. AGPAT2 plays a critical role in the synthesis of glycerophospholipids and triglycerides required for lipid droplet formation. Another protein, seipin (encoded by BSCL2 gene), has been found to induce lipid droplet fusion. CAV1 is an integral component of caveolae and might contribute towards lipid droplet formation. PPARγ and AKT2 play important role in adipogenesis and lipid synthesis. In this review, we discuss and speculate about the contribution of various lipodystrophy genes and their products in the lipid droplet formation.     

Understanding Human Glycosylation Disorders: Biochemistry Leads the Charge

Nearly 70 inherited human glycosylation disorders span a breathtaking clinical spectrum, impacting nearly every organ system and launching a family-driven diagnostic odyssey. Advances in genetics, especially next generation sequencing, propelled discovery of many glycosylation disorders in single and multiple pathways. Interpretation of whole exome sequencing results, insights into pathological mechanisms, and possible therapies will hinge on biochemical analysis of patient-derived materials and animal models. Biochemical diagnostic markers and readouts offer a physiological context to confirm candidate genes. Recent discoveries suggest novel perspectives for textbook biochemistry and novel research opportunities. Basic science and patients are the immediate beneficiaries of this bidirectional collaboration.     

Primary hyperoxalurias: Disorders of glyoxylate detoxification

Glyoxylate detoxification is an important function of human peroxisomes. Glyoxylate is a highly reactive molecule, generated in the intermediary metabolism of glycine, hydroxyproline and glycolate mainly. Glyoxylate accumulation in the cytosol is readily transformed by lactate dehydrogenase into oxalate, a dicarboxylic acid that cannot be metabolized by mammals and forms tissue-damaging calcium oxalate crystals. Alanine-glyoxylate aminotransferase, a peroxisomal enzyme in humans, converts glyoxylate into glycine, playing a central role in glyoxylate detoxification. Cytosolic and mitochondrial glyoxylate reductase also contributes to limit oxalate production from glyoxylate. Mitochondrial hydroxyoxoglutarate aldolase is an important enzyme of hydroxyproline metabolism. Genetic defect of any of these enzymes of glyoxylate metabolism results in primary hyperoxalurias, severe human diseases in which toxic levels of oxalate are produced by the liver, resulting in progressive renal damage. Significant advances in the pathophysiology of primary hyperoxalurias have led to better diagnosis and treatment of these patients, but current treatment relies mainly on organ transplantation. It is reasonable to expect that recent advances in the understanding of the molecular mechanisms of disease will result into better targeted therapeutic options in the future. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.