Gene/Protein Disease Symptom Drug Enzyme Compound
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Pseudoxanthoma elasticum (PXE) is a relatively rare heritable disorder affecting the skin, eyes and cardiovascular system, with considerable morbidity and mortality. The disease affects the elastic fibers of affected organs, which become progressively calcified. Thus, PXE has been considered as a prototypic heritable connective tissue disorder affecting the elastic fiber system. Recently, PXE has been linked to mutations in the MRP6/ABCC6 gene, a member of the ABC transporter family, expressed primarily in the liver and the kidneys. This information, together with clinical observations suggesting environmental, hormonal and/or dietary modulation of the disease, raises the intriguing possibility that PXE is a primary metabolic disorder at the environment-genome interface.
Trends Mol Med 2001 Jan
PMID:Molecular genetics of pseudoxanthoma elasticum: a metabolic disorder at the environment-genome interface? 1142 82

Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype--phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.
Hum Mol Genet 2001 Jul 15
PMID:Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. 1146 77

The intracellular homeostasis is controlled by different membrane transporters. Organic cation transporters function primarily in the elimination of cationic drugs, endogenous amines, and other xenobiotics in tissues such as the kidney, intestine, and liver. Among these molecules, carnitine is an endogenous amine which is an essential cofactor for mitochondrial beta-oxidation. Recently, a new family of transporters, named OCT (organic cation transporters) has been described. In this minireview, we present the recent knowledge about OCT and focus on carnitine transport, more particularly by the OCTN2. The importance of this sodium-dependent carnitine cotransporter, OCTN2, comes from various recently reported mutations in the gene which give rise to the primary systemic carnitine deficiency (SCD; OMIM 212140). The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia. Most of the OCTN2 mutations identified in humans with SCD result in loss of carnitine transport function. Identifying these mutations will allow an easy targeting of the SCD syndrome. The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described. These mice have a mutation in the gene encoding the mouse carnitine transporter octn2. Although various OCTN carnitine transporters have been identified and functionally characterized, their membrane localization and regulation are still unknown and must be investigated. This knowledge will also help in designing new drugs that regulate carnitine transport activity.
Mol Genet Metab 2001 Aug
PMID:Carnitine transport by organic cation transporters and systemic carnitine deficiency. 1150 10

We are now approaching the reality of success in gene therapy as our knowledge of the genetic basis of disease continues to grow, coupled with improved delivery methods for therapeutic nucleic acid molecules. It is apparent that gene therapy can be divided into two specific and very different approaches in which gene replacement, or augmentation, is differentiated from gene repair. In fact, gene augmentation is characterized by the delivery of the coding sequence of the gene of interest in an expression cassette. In contrast, gene repair differs in that the process targets for correction of the mutation responsible for the genetic disorder. The in situ repair of a gene has many advantages over conventional replacement methods. This review will concentrate on the various strategies currently available for gene repair. The potential benefits of correction versus augmentation will be addressed and possible future developments outlined.
Curr Opin Mol Ther 2001 Aug
PMID:Targeted gene correction strategies. 1152 56

X-linked adrenoleukodystrophy (ALD) is the most frequently seen genetic disorder involving the myelin of the central nervous system. The cerebral form affects mainly boys between five to 12 years, leading to vegetative state or death within two to four years. The adult form affects the spinal cord, leading to severe paraplegia often complicated by cerebral demyelination. The ALD gene encodes an ATP-binding cassette transporter involved in the transport of very long chain fatty acids into peroxysomes. Specific subpopulations of oligodendrocytes and microglia are particularly affected by the ALD gene mutation and thus should be the target cells of gene therapy approaches. Two different and potentially complementary therapeutic strategies are currently evaluated. The first approach aims at replacing the endogenous brain microglia from patients by autotransplantation of genetically corrected hematopoietic stem cells using a lentiviral vector. The second approach aims at targeting directly the ALD gene into brain glial cells using stereotactic injections of viral vectors.
Curr Opin Mol Ther 2001 Aug
PMID:Gene therapy strategies for X-linked adrenoleukodystrophy. 1152 59

Few autosomal recessive disorders display the degree of pleiotropism and genetic heterogeneity found in Bardet-Biedl syndrome (BBS), a genetic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, cognitive impairment and gonadal and renal dysgenesis. This relatively rare condition has been reported frequently, but we have only recently begun to appreciate the genetic complexities that give rise to this constellation of clinical findings. During the last 12 months, the first three of at least six BBS genes have been identified, providing us for the first time with the ability to formulate hypotheses regarding the molecular etiology of the disorder. Here we review the key elements of the phenotype and discuss the significance of the discovery of the first three BBS genes on the effort to identify the cellular causes of this syndrome.
Hum Mol Genet 2001 Oct 01
PMID:Exploring the molecular basis of Bardet-Biedl syndrome. 1167 13

This review presents our current knowledge on the genetic and phenotypic aspects of mitochondrial complex II gene defects. The mutations of the complex II subunits cause two strikingly different group of disorders, revealing a phenotypic dichotomy. Genetic disorders of the mitochondrial respiratory chain are often characterized by hypotonia, growth retardation, cardiomyopathy, myopathy, neuropathy, organ failure, and metabolic derangement. These disorders are transmitted through maternal lineage if the defective gene is located in the mitochondrial genome or may follow a Mendelian pattern if it is in the nucleus. Mitochondrial complex II (succinate:ubiquinone oxidoreductase) is the smallest complex in the respiratory chain and is composed of four subunits encoded by nuclear genes SDHA, SDHB, SDHC, and SDHD. Complex II oxidizes succinate to fumarate in the Krebs cycle and is involved in the mitochondrial electron transport chain. SDHA and SDHB encode the flavoprotein and iron-sulfur proteins, respectively, and SDHC and SDHD encode the two hydrophobic membrane-spanning subunits. While mutations in SDHA display a phenotype resembling other mitochondrial and Krebs cycle gene defects, those in SDHB, SDHC and SDHD cause hereditary paraganglioma. Paraganglioma is characterized by slow-growing vascular tumors of the paraganglionic tissue (i.e., adrenal and extra-adrenal paragangliomas, including those in the head and neck, mediastinum, abdomen, and pheochromocytomas). Paraganglioma caused by SDHD mutations occurs exclusively after paternal transmission, suggesting that genomic imprinting influences gene expression. Association of a mitochondrial gene defect with tumorigenesis expands the phenotypic spectrum of mitochondrial diseases and adds genomic imprinting as a new transmission mode in mitochondrial genetics. The phenotypic features of complex II gene mutations suggest that whereas the catalytic subunit SDHA mutations may compromise the Krebs cycle, those in other structural subunits may affect oxygen sensing and signaling.
J Mol Med (Berl) 2001 Sep
PMID:Phenotypic dichotomy in mitochondrial complex II genetic disorders. 1169 62

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a range of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS and other related disorders of connective tissue collectively termed type-1 fibrillinopathies. Fibrillin-1 is a main component of the 10- to 12-nm extracellular microfibrils that are important for elastogenesis, elasticity, and homeostasis of elastic fibers. Mutations in fibrillin-1 are hypothesized to exert their effects by dominant negative mechanisms, but recent work has also emphasized the potential role of proteases and disturbances in tissue homeostasis in the pathogenesis of the MFS. This article provides an overview of the clinical aspects of the MFS and current thinking on the pathogenesis of this disorder.
Cell Mol Life Sci 2001 Oct
PMID:The molecular pathogenesis of the Marfan syndrome. 1170 95

Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.
Hum Mol Genet 2001 Nov 01
PMID:Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. 1172 52

Fanconi anemia (FA) is a human genetic disorder characterized by hypersensitivity to DNA crosslinking agents. Its cellular phenotypes include increased chromosome breakage and a marked cell-cycle delay with 4N DNA content after introduction of interstrand DNA crosslinks (ICL). To further understand the nature of this delay previously described as a G2/M arrest, we introduced ICL specifically during G2 and monitored the cells for passage into mitosis. Our results showed that, even at the highest doses, postreplication ICL produced neither G2/M arrest nor chromosome breakage in FA-A or FA-C cells. This suggests that, similar to wild-type cells, DNA replication is required to trigger both responses. Therefore, the 4N cell DNA content observed in FA cells after ICL treatment also represents incomplete DNA replication and arrest in late S phase. FA fibroblasts from complementation groups A and C were able to recover from the ICL-induced cell-cycle arrest, but took approximately 3 times longer than controls. These results indicate that the FA pathway is required for the efficient resolution of ICL-induced S-phase arrest.
Mol Genet Metab 2001 Dec
PMID:The 4N cell cycle delay in Fanconi anemia reflects growth arrest in late S phase. 1174 45


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