Molecular genetics of heterotaxy syndromes

PURPOSE OF REVIEW: Heterotaxy is a complex set of birth defects in which the normal concordance of asymmetric thoracic and abdominal organs is disturbed. In this review the authors summarize recent research on the etiology of heterotaxy syndromes. Improved understanding of the genetic control of left-right patterning in the early embryo is leading to the identification of candidate genes that may be mutated in heterotaxy patients, and epidemiologic studies are helping to define nongenetic mechanisms of embryopathy. RECENT FINDINGS: Several genes have now been implicated in heterotaxy and related isolated congenital heart malformations. These studies indicate that heterotaxy can be caused by single gene mutations. They also demonstrate that there is probably extensive locus heterogeneity. Heterotaxy may be caused by teratogenic exposures, especially maternal diabetes. Isolated congenital heart defects resulting from isomerisms and disturbed looping may be caused by mutations in genes that control early left-right patterning and the earliest steps in cardiogenesis. Genes currently implicated in human heterotaxy include ZIC3, LEFTYA, CRYPTIC, and ACVR2B. Roles for NKX2.5 and CRELDA are suggested by recent case reports. SUMMARY: Active research on the etiology of heterotaxy is leading to a reformulation of the likely etiologies. Its complex inheritance likely results from a mix of teratogenic and single gene disorders with variable expression and incomplete penetrance.     

Correction of symptoms of platelet storage pool deficiency in animal models for Chediak-Higashi syndrome and Hermansky-Pudlak syndrome

Two human diseases of platelet storage pool deficiency (SPD), Hermansky- Pudlak syndrome and Chediak-Higashi syndrome, are recessively inherited disorders characterized by hypopigmentation, prolonged bleeding, and normal platelet counts accompanied by a reduction in dense granule number. We have recently described seven independent recessive mutations in the mouse regulated by separate genes which are likely animal models for human SPD. Reciprocal bone marrow transplants were carried out between normal C57BL/6J mice and two of these mutants, beige and pallid, in order to test whether the platelet defects are due to a defect in platelet progenitor cells or to humoral factors. Normal and congenic mutant mice were transplanted with marrow after 950 rad whole body radiation. The long bleeding times and low serotonin concentrations of the two mutants were converted to normal values after transplantation with normal marrow. Likewise, normal mice displayed symptoms of SPD when transplanted with mutant marrow. These studies demonstrate that with each of the two mutations, platelet SPD results from a defect in bone marrow precursor cells. Also, the studies suggest that in severe cases, platelet SPD may be successfully treated by bone marrow transplantation.     

The genetics of ACTH resistance syndromes

Inherited adrenocorticotropin (ACTH) resistance diseases are rare and include triple A syndrome and familial glucocorticoid deficiency (FGD). These conditions show genetic heterogeneity, i.e., the identical clinical phenotype may result from defects in more than one gene. Clinically, FGD is characterized only by ACTH resistance, while the triple A syndrome exhibits a variety of additional clinical features. FGD is caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) and the recently identified melanocortin 2 receptor accessory protein (MRAP) genes. In addition, linkage to a locus on chromosome 8 has been demonstrated. The identification of further genes in ACTH resistance syndromes may reveal novel aspects of MC2R signalling and trafficking. This review will summarize the clinical, biochemical and genetic aspects of these rare but informative diseases.     

Molecular genetics of PKU

This review summarizes the isolation of rat phenylalanine hydroxylase mRNA and its use in the synthesis of its cDNA. As rat cDNA cross-hybridized with human phenylalanine hydroxylase mRNA, the rat cDNA probe was used to screen a human liver cDNA library. A partial length cDNA human phenylalanine hydroxylase probe was obtained which showed restriction fragment length polymorphism (RFLP) with 3 restriction enzymes and was successfully used to trace the transmission of the mutant gene in PKU families with one or more affected children. Recently the partial-length cDNA probe has been used to isolate a full-length cDNA probe for human phenylalanine hydroxylase. Gene transfer experiments with the full-length cDNA have led to expression of human phenylalanine hydroxylase in eukaryotic cultured cells and in recombinant bacteria which normally do not express phenylalanine hydroxylase activity. The full-length cDNA of human phenylalanine hydroxylase has been sequenced, uncovering the nucleic acid sequence of the exons of the human phenylalanine hydroxylase gene, as well as the most likely amino acid structure of the human phenylalanine hydroxylase enzyme. The full-length cDNA probe has 10 identifiable binding sites for restriction enzymes that show RFLP. These additional RFLPs have enabled haplotype analyses of the normal and mutant phenylalanine hydroxylase genes in PKU families. Haplotype analyses in Danish PKU families revealed 12 different haplotypes. However, of 132 chromosomes analysed from 66 obligate heterozygotes, 59 out of 66 PKU genes were associated with only 4 haplotypes. Cosmid cloning and preliminary characterization of the human phenylalanine hydroxylase gene have identified 13 exons distributed across a gene that is more than 190 kb in length. In β-thalassaemia, distinct mutations in the β-globin locus are associated with specific RFLP haplotypes within a given population. As in thalassaemia such an association forms a strategy for cloning and sequence characterization of mutant phenylalanine hydroxylase genes derived from each haplotype. If the PKU genes in the Danish population are the result of mutiple mutations which occurred on chromosomes of the most common haplotypes, the same strategy is potentially applicable for the molecular characterization of the various types of phenylalanine hydroxylase deficiency.     

Molecular genetics of ABO

This year commemorates the 100th anniversary of the discovery of the ABO blood group system by Karl Landsteiner. His findings of red cell agglutination by serum and recognition of blood groups laid the scientific basis for safe practice of blood transfusion. Even though dozens of blood systems have been identified, the ABO system still remains to be one of the most important systems in transfusion medicine. In 1990, we elucidated the molecular genetic basis of three major alleles at the ABO locus. Since then we have witnessed the progress in our understanding of ABO genes and A and B glycosyltransferases specified by a variety of functional alleles at this locus. Mutations affecting the activity and specificity of the enzymes have been identified. Not only has ABO genotyping become possible, but it has also become possible to genetically engineer the activity and specificity of the enzymes. We are now at a point of embarking upon the quest of understanding the functional significance of ABO polymorphism.     

Molecular genetics of cardiomyopathies

In the last decade our understanding of cardiac pathophysiology has experienced significant advances linked to major advances in molecular genetics. Although many genes are associated today with cardiac diseases, the genetics of both hypertrophic cardiomyopathy and dilated cardiomyopathy have generated great interest. The familial nature of the disease in some patients has been very useful in this regard. In addition, there are also excellent experimental models to study the implications of the genetic abnormalities. Altogether the study of the molecular genetics of the cardiomyopathies should provide not only prognostic information but also new therapeutic alternatives.     

Molecular genetics of HLA

A review of the molecular genetics of the HLA gene complex from a tissue typer's point of view.     

Molecular genetics and subjective well-being

Subjective well-being (SWB) is a major topic of research across the social sciences. Twin and family studies have found that genetic factors may account for as much as 30–40% of the variance in SWB. Here, we study genetic contributions to SWB in a pooled sample of ≈11,500 unrelated, comprehensively-genotyped Swedish and Dutch individuals. We apply a recently developed method to estimate “common narrow heritability”: the fraction of variance in SWB that can be explained by the cumulative additive effects of genetic polymorphisms that are common in the population. Our estimates are 5–10% for single-question survey measures of SWB, and 12–18% after correction for measurement error in the SWB measures. Our results suggest guarded optimism about the prospects of using genetic data in SWB research because, although the common narrow heritability is not large, the polymorphisms that contribute to it could feasibly be discovered with a sufficiently large sample of individuals.     

Molecular biology and the prolonged QT syndromes

The prolonged QT syndromes are characterized by prolongation of the QT interval corrected for heart rate (QTc) on the surface electrocardiogram associated with T-wave abnormalities, relative bradycardia, and ventricular tachyarrhythmias, including polymorphic ventricular tachycardia and torsades de pointes. These patients tend to present with episodes of syncope, seizures, or sudden death typically triggered by exercise, emotion, noise, or, in some cases, sleep. These disorders of cardiac repolarization are commonly inherited, with the autosomal dominant form, Romano-Ward syndrome, most common. A rare autosomal recessive form associated with sensorineural deafness, Jervell and Lange-Nielsen syndrome, in which the cardiac disorder is autosomal dominant and deafness is a recessive trait, also occurs. The underlying genetic causes of these forms of prolonged QT interval syndromes are heterogeneous, with at least seven genes responsible for the clinical syndromes. All of the five genes identified to date encode ion channel proteins, suggesting this to be an ion channelopathy. In this review, the genetic basis of the prolonged QT interval syndromes will be discussed, genotype-phenotype correlations identified, and the approaches to genetic testing and treatments will be outlined.     

Signs and genetics of rare cancer syndromes with gastroenterological features

Although the genetic bases of most hereditary cancer syndromes are known, and genetic tests are available for them, the incidence of the most rare of these syndromes is likely underestimated, partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs, though not necessarily tumors, that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis, and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.