Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics.
Ontology highlight
ABSTRACT:
SUBMITTER: Huizing M
PROVIDER: S-EPMC2755194 | biostudies-literature | 2008
REPOSITORIES: biostudies-literature
Publications
Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics.
Huizing Marjan M Helip-Wooley Amanda A Westbroek Wendy W Gunay-Aygun Meral M Gahl William A WA
Annual review of genomics and human genetics 20080101
Lysosome-related organelles (LROs) are a heterogeneous group of vesicles that share various features with lysosomes, but are distinct in function, morphology, and composition. The biogenesis of LROs employs a common machinery, and genetic defects in this machinery can affect all LROs or only an individual LRO, resulting in a variety of clinical features. In this review, we discuss the main components of LRO biogenesis. We also summarize the function, composition, and resident cell types of the m ...[more]
Similar Datasets
Project description:Gut granules are specialized lysosome-related organelles that act as sites of fat storage in Caenorhabditis elegans intestinal cells. We identified mutations in a gene, glo-3, that functions in the formation of embryonic gut granules. Some glo-3(-) alleles displayed a complete loss of embryonic gut granules, while other glo-3(-) alleles had reduced numbers of gut granules. A subset of glo-3 alleles led to mislocalization of gut granule contents into the intestinal lumen, consistent with a defect in intracellular trafficking. glo-3(-) embryos lacking gut granules developed into adults containing gut granules, indicating that glo-3(+) function may be differentially required during development. We find that glo-3(+) acts in parallel with or downstream of the AP-3 complex and the PGP-2 ABC transporter in gut granule biogenesis. glo-3 encodes a predicted membrane-associated protein that lacks obvious sequence homologs outside of nematodes. glo-3 expression initiates in embryonic intestinal precursors and persists almost exclusively in intestinal cells through adulthood. GLO-3GFP localizes to the gut granule membrane, suggesting it could play a direct role in the trafficking events at the gut granule. smg-1(-) suppression of glo-3(-) nonsense alleles indicates that the C-terminal half of GLO-3, predicted to be present in the cytoplasm, is not necessary for gut granule formation. Our studies identify GLO-3 as a novel player in the formation of lysosome-related organelles.
| S-EPMC2567386 | biostudies-literature
Project description:Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mutations in loci other than MECP2 have also been found in individuals that have been labeled as atypical RTT. Among them, a mutation in the gene forkhead box G1 (FOXG1) has been involved in the molecular aetiology of the congenital variant of RTT. The FOXG1 gene encodes a winged-helix transcriptional repressor essential for the development of the ventral telencephalon in embryonic forebrain. Later, FOXG1 continues to be expressed in neurogenetic zones of the postnatal brain. Although RTT affects quasi-exclusively girls, FOXG1 mutations have also been identified in male patients. As far as we know, about 12 point mutations and 13 cases with FOXG1 molecular abnormalities (including translocation, duplication and large deletion on the chromosome 14q12) have been described in the literature. Affected individuals with FOXG1 mutations have shown dysmorphic features and Rett-like clinical course, including normal perinatal period, postnatal microcephaly, seizures and severe mental retardation. Interestingly, the existing animal models of FOXG1 deficiency showed similar phenotype, suggesting that animal models may be a fascinating model to understand this human disease. Here, we describe the impacts of FOXG1 mutations and their associated phenotypes in human and mouse models.
| S-EPMC3366704 | biostudies-literature
Project description:Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. To date, with more than 80 reported cases, the phenotype of CDKL5-related encephalopathy is better defined. The main features consist of early-onset seizures starting before 5 months of age, severe mental retardation with absent speech and Rett-like features such as hand stereotypies and deceleration of head growth. On the other hand, neuro-vegetative signs and developmental regression are rare in CDKL5 mutation patients. The CDKL5 gene encodes a serine threonine kinase protein which is characterized by a catalytic domain and a long C-terminal extension involved in the regulation of the catalytic activity of CDKL5 and in the sub-nuclear localization of the protein. To our knowledge, more than 70 different point mutations have been described including missense mutations within the catalytic domain, nonsense mutations causing the premature termination of the protein distributed in the entire open reading frame, splice variants, and frameshift mutations. Additionally, CDKL5 mutations have recently been described in 7 males with a more severe epileptic encephalopathy and a worse outcome compared to female patients. Finally, about 23 male and female patients have been identified with gross rearrangements encompassing all or part of the CDKL5 gene, with a phenotype reminiscent of CDKL5-related encephalopathy combined with dysmorphic features. Even if recent data clearly indicate that CDKL5 plays an important role in brain function, the protein remains largely uncharacterized. Phenotype-genotype correlation is additionally hampered by the relatively small number of patients described.
| S-EPMC3366705 | biostudies-literature
Project description:Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.
| S-EPMC9688865 | biostudies-literature
Project description:ABC transporters couple ATP hydrolysis to the transport of substrates across cellular membranes. This protein superfamily has diverse activities resulting from differences in their cargo and subcellular localization. Our work investigates the role of the ABCG family member WHT-2 in the biogenesis of gut granules, a Caenorhabditis elegans lysosome-related organelle. In addition to being required for the accumulation of birefringent material within gut granules, WHT-2 is necessary for the localization of gut granule proteins when trafficking pathways to this organelle are partially disrupted. The role of WHT-2 in gut granule protein targeting is likely linked to its function in Rab GTPase localization. We show that WHT-2 promotes the gut granule association of the Rab32 family member GLO-1 and the endolysosomal RAB-7, identifying a novel function for an ABC transporter. WHT-2 localizes to gut granules where it could play a direct role in controlling Rab localization. Loss of CCZ-1 and GLO-3, which likely function as a guanine nucleotide exchange factor (GEF) for GLO-1, lead to similar disruption of GLO-1 localization. We show that CCZ-1, like GLO-3, is localized to gut granules. WHT-2 does not direct the gut granule association of the GLO-1 GEF and our results point to WHT-2 functioning differently than GLO-3 and CCZ-1 Point mutations in WHT-2 that inhibit its transport activity, but not its subcellular localization, lead to the loss of GLO-1 from gut granules, while other WHT-2 activities are not completely disrupted, suggesting that WHT-2 functions in organelle biogenesis through transport-dependent and transport-independent activities.
| S-EPMC7017009 | biostudies-literature
Project description:Cell type-specific modifications of conventional endosomal trafficking pathways lead to the formation of lysosome-related organelles (LROs). C. elegans gut granules are intestinally restricted LROs that coexist with conventional degradative lysosomes. The formation of gut granules requires the Rab32 family member GLO-1. We show that the loss of glo-1 leads to the mistrafficking of gut granule proteins but does not significantly alter conventional endolysosome biogenesis. GLO-3 directly binds to CCZ-1 and they both function to promote the gut granule association of GLO-1, strongly suggesting that together, GLO-3 and CCZ-1 activate GLO-1. We found that a point mutation in GLO-1 predicted to spontaneously activate, and function independently of it guanine nucleotide exchange factor (GEF), localizes to gut granules and partially restores gut granule protein localization in ccz-1(-) and glo-3(-) mutants. CCZ-1 forms a heterodimeric complex with SAND-1(MON1), which does not function in gut granule formation, to activate RAB-7 in trafficking pathways to conventional lysosomes. Therefore, our data suggest a model whereby the function of a Rab GEF can be altered by subunit exchange. glo-3(-) mutants, which retain low levels of GLO-3 activity, generate gut granules that lack GLO-1 and improperly accumulate RAB-7 in a SAND-1 dependent process. We show that GLO-1 and GLO-3 restrict the distribution of RAB-7 to conventional endolysosomes, providing insights into the segregation of pathways leading to conventional lysosomes and LROs.
| S-EPMC6268011 | biostudies-literature
Project description:Caenorhabditis elegans gut granules are intestine specific lysosome-related organelles with birefringent and autofluorescent contents. We identified pgp-2, which encodes an ABC transporter, in screens for genes required for the proper formation of gut granules. pgp-2(-) embryos mislocalize birefringent material into the intestinal lumen and are lacking in acidified intestinal V-ATPase-containing compartments. Adults without pgp-2(+) function similarly lack organelles with gut granule characteristics. These cellular phenotypes indicate that pgp-2(-) animals are defective in gut granule biogenesis. Double mutant analysis suggests that pgp-2(+) functions in parallel with the AP-3 adaptor complex during gut granule formation. We find that pgp-2 is expressed in the intestine where it functions in gut granule biogenesis and that PGP-2 localizes to the gut granule membrane. These results support a direct role of an ABC transporter in regulating lysosome biogenesis. Previously, pgp-2(+) activity has been shown to be necessary for the accumulation of Nile Red-stained fat in C. elegans. We show that gut granules are sites of fat storage in C. elegans embryos and adults. Notably, levels of triacylglycerides are relatively normal in animals defective in the formation of gut granules. Our results provide an explanation for the loss of Nile Red-stained fat in pgp-2(-) animals as well as insight into the specialized function of this lysosome-related organelle.
| S-EPMC1805080 | biostudies-literature
Project description:Lysosomes are membrane-bound organelles that contain acid hydrolases that degrade cellular proteins, lipids, nucleic acids, and oligosaccharides, and are important for cellular maintenance and protection against age-related decline. Lysosome related organelles (LROs) are specialized lysosomes found in organisms from humans to worms, and share many of the features of classic lysosomes. Defective LROs are associated with human immune disorders and neurological disease. Caenorhabditis elegans LROs are the site of concentration of vital dyes such as Nile red as well as age-associated autofluorescence. Even though certain short-lived mutants have high LRO Nile red and high autofluorescence, and other long-lived mutants have low LRO Nile red and low autofluorescence, these two biologies are distinct. We identified a genetic pathway that modulates aging-related LRO phenotypes via serotonin signaling and the gene kat-1, which encodes a mitochondrial ketothiolase. Regulation of LRO phenotypes by serotonin and kat-1 in turn depend on the proton-coupled, transmembrane transporter SKAT-1. skat-1 loss of function mutations strongly suppress the high LRO Nile red accumulation phenotype of kat-1 mutation. Using a systems approach, we further analyzed the role of 571 genes in LRO biology. These results highlight a gene network that modulates LRO biology in a manner dependent upon the conserved protein kinase TOR complex 2. The results implicate new genetic pathways involved in LRO biology, aging related physiology, and potentially human diseases of the LRO.
| S-EPMC3812091 | biostudies-literature
Project description:Complete and accurate profiling of cellular organelle proteomes, while challenging, is important for the understanding of detailed cellular processes at the organelle level. Mass spectrometry technologies coupled with bioinformatics analysis provide an effective approach for protein identification and functional interpretation of organelle proteomes. In this study, we have compiled human organelle reference datasets from large-scale proteomic studies and protein databases for 7 lysosome-related organelles (LROs), as well as the endoplasmic reticulum and mitochondria, for comparative organelle proteome analysis. Heterogeneous sources of human organelle proteins and rodent homologs are mapped to human UniProtKB protein entries based on ID and/or peptide mappings, followed by functional annotation and categorization using the iProXpress proteomic expression analysis system. Cataloging organelle proteomes allows close examination of both shared and unique proteins among various LROs and reveals their functional relevance. The proteomic comparisons show that LROs are a closely related family of organelles. The shared proteins indicate the dynamic and hybrid nature of LROs, while the unique transmembrane proteins may represent additional candidate marker proteins for LROs. This comparative analysis, therefore, provides a basis for hypothesis formulation and experimental validation of organelle proteins and their functional roles.
| S-EPMC1828028 | biostudies-literature
Project description:Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained.
| S-EPMC2563177 | biostudies-literature