X-Linked Adrenoleukodystrophy: Genes,Mutations, and Phenotypes

X-linked adrenoleukodystrophy (X-ALD) is a complex and perplexing neurodegenerative disorder. The metabolic abnormality, elevated levels of very long-chain fatty acids in tissues and plasma, and the biochemical defect, reduced peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity, are ubiquitous features of the disease. However, clinical manifestations are highly variable with regard to time of onset, site of initial pathology and rate of progression. In addition, the abnormal gene in X-ALD is not the gene for VLCS. Rather, it encodes a peroxisomal membrane protein with homology to the ATP-binding cassette (ABC) transmembrane transporter superfamily of proteins. The X-ALD protein (ALDP) is closely related to three other peroxisomal membrane ABC proteins. In this report we summarize all known X-ALD mutations and establish the lack of an X-ALD genotype/phenotype correlation. We compare the evolutionary relationships among peroxisomal ABC proteins, demonstrate that ALDP forms homodimers with itself and heterodimers with other peroxisomal ABC proteins and present cDNA complementation studies suggesting that the peroxisomal ABC proteins have overlapping functions. We also establish that there are at least two peroxisomal VLCS activities, one that is ALDP dependent and one that is ALDP independent. Finally, we discuss variable expression of the peroxisomal ABC proteins and ALDP independent VLCS in relation to the variable clinical presentations of X-ALD.     

Genetics and Molecular Biology of Mouse Pigmentation

The formation of mouse coat color is a relatively complex developmental process that is affected by a large number of mutations, both naturally occurring and induced. The cloning of the genes in which these mutations occur and the elucidation of the mechanisms by which these mutations disrupt the normal pigmentation pattern is leading to an understanding of the way interactions between gene products lead to a final phenotype.     

Application of Molecular Biology and Genetics in Endocrinology

ObjectiveTo review the growing impact of molecular biology and genetics on clinical endocrinology.MethodsMedical literature, databases, and Web sites describing genetics and genomic medicine with relevance for clinical endocrinology were reviewed.ResultsMany monogenic disorders can now be explained at the molecular level and the diagnosis can be established through mutational analysis. The ability to establish a molecular diagnosis is relevant for carrier detection and genetic counseling. In contrast to the significant advances in monogenic disorders, the current knowledge about the genetic components contributing to the pathogenesis of complex disorders is still relatively modest and is a major focus of current research efforts. Molecular biology already has an important impact on therapy in endocrine disorders. A broad spectrum of recombinant peptides and proteins are used in daily practice, eg, insulin and insulin analogues. Moreover, the increasingly detailed understanding of the molecular pathogenesis of cancer is leading to the development of novel and more specific inhibitors. While genetic testing has many advantages, it is important that physicians and patients are aware of potential limitations. They include, among others, technical limitations and allelic and nonallelic heterogeneity. These limitations need to be discussed in detail with patients and relatives, and it is often useful to involve a genetic counselor before obtaining informed consent by the individuals undergoing testing.ConclusionMolecular biology and genetics play an increasingly important role for the diagnosis and therapy of endocrine disorders. Challenges for the future include the elucidation of the genetic components contributing to complex disorders, eg, diabetes mellitus type 2, and the development of cheaper and comprehensive DNA sequencing technologies. Lastly, it is important that there is continuing attention directed towards the ethical, social, and legal aspects surrounding genetic medicine. (Endocr Pract, 2007;13: 534-541)     

Genetics and Molecular Biology of Tuberous Sclerosis Complex

Tuberous Sclerosis Complex is a multisystem disorder exhibiting a wide range of manifestations characterized by tumour-like lesions called hamartomas in the brain, skin, eyes, heart, lungs and kidneys. Tuberous Sclerosis Complex is genetically determined with an autosomal dominant inheritance and is caused by inactivating mutations in either the TSC1 or TSC2 genes. TSC1/2 genes play a fundamental role in the regulation of phosphoinositide 3-kinase (PI3K) signalling pathway, inhibiting the mammalian target of rapamycin (mTOR) through activation of the GTPase activity of Rheb. Mutations in TSC1/2 genes impair the inhibitory function of the hamartin/tuberin complex, leading to phosphorylation of the downstream effectors of mTOR, p70 S6 kinase (S6K), ribosomal protein S6 and the elongation factor binding protein 4E-BP1, resulting in uncontrolled cell growth and tumourigenesis.     

The Physiology, Genetics and Molecular Biology of Plant Aluminum Resistance and Toxicity

Aluminum (Al) toxicity is the primary factor limiting crop production on acidic soils (pH values of 5 or below), and because 50% of the world’s potentially arable lands are acidic, Al toxicity is a very important limitation to worldwide crop production. This review examines our current understanding of mechanisms of Al toxicity, as well as the physiological, genetic and molecular basis for Al resistance. Al resistance can be achieved by mechanisms that facilitate Al exclusion from the root apex (Al exclusion) and/or by mechanisms that confer the ability of plants to tolerate Al in the plant symplasm (Al tolerance). Compelling evidence has been presented in the literature for a resistance mechanism based on exclusion of Al due to Al-activated carboxylate release from the growing root tip. More recently, researchers have provided support for an additional Al-resistance mechanism involving internal detoxification of Al with carboxylate ligands (deprotonated organic acids) and the sequestration of the Al-carboxylate complexes in the vacuole. This is a field that is entering a phase of new discovery, as researchers are on the verge of identifying some of the genes that contribute to Al resistance in plants. The identification and characterization of Al resistance genes will not only greatly advance our understanding of Al-resistance mechanisms, but more importantly, will be the source of new molecular resources that researchers will use to develop improved crops better suited for cultivation on acid soils.     

Statistics in Human Genetics and Molecular Biology by REILLY,C.

Statistics in Human Genetics and Molecular Biology (C. Reilly) Xiang‐Yang Lou and David B. Allison Meta‐Analysis and Combining Information in Genetics and Genomics (R. Guerra and D. R. Goldstein) Peter H. Westfall Multivariate Nonparametric Methods with R. An Approach Based on Spatial Signs and Ranks (H. Oja) Mia Hubert Bayesian Analysis for Population Ecology (R. King, B. J. T. Morgan, O. Gimenez, and S. Brooks) Simon Bonner The Oxford Handbook of Functional Data Analysis (F. Ferraty and Y. Romain, Editors) Paul H. C. Eilers Design and Analysis of Experiments with SAS (J. Lawson) Francis Giesbrecht Spatial Statistics and Modeling (C. Gaetan and X. Guyon) Paulo J. Ribeiro Jr. Applied Statistical Genetics with R: For Population‐Based Association Studies (A. S. Foulkes) Kui Zhang     

Introductory Biology and Genetics CD

D G Mackean Available from DonMackean@biology-resources.com or download an order form from www.biology-resources.com £8.00 Reviewed by Sue Howarth