Cardiomyopathy: a systematic review of disease-causing mutations in myosin heavy chain 7 and their phenotypic manifestations.

BACKGROUND: Mutations in myosin heavy chain 7 (MYH7) commonly cause cardiomyopathy. However, the relationship between mutation location, cardiomyopathy type, change in amino acid composition and disease severity is poorly understood. This systematic review aims to provide, on a large scale, important insights into the role mutations in MYH7 play in cardiomyopathy. METHODS: The literature was searched from 1966 to March 2009. The mutation location, type of mutation and disease type and severity were documented. When the severity of disease was known, the change in charge and hydropathy of the mutation was determined. Where appropriate, either a chi(2) test was used or a relative risk ratio was calculated in order to evaluate the data. RESULTS: The data presented in this study demonstrate that there are proportionately more mutations in the head and neck regions of this gene than in the tail. Importantly, mutations in the head of the gene, those that cause large changes in the hydropathy of the amino acid and non-conservative mutations are more likely to lead to a severe phenotype. CONCLUSIONS: This study suggests that mutation location in the MYH7 gene and changes in amino acid composition can have a negative impact on the disease outcome in individuals with cardiomyopathy.

A survey of medical students on the impact of a new digital imaging library in the dissection room.

Radiology has a recognised role in undergraduate anatomy education. The recent digitalisation of radiology has created new learning opportunities involving techniques such as image labelling, 3D reconstruction, and multiplanar reformatting. An opportunity was identified at the University of Nottingham to create a digital library of normal radiology images as a learner-driven adjunct in anatomy dissection sessions. We describe the process of creating a de novo digital library by sourcing images for presentation at computer workstations. Students' attitudes towards this new resource were assessed using a questionnaire which used a 5 point Likert scale and also offered free text responses. One hundred and forty-one out of 260 students (54%) completed the questionnaire. The most notable findings were: a positive response to the relevance of imaging to the session topics (median score 4), strong agreement that images should be available on the university website (median score 5), and disagreement that enough workstations were available (median score 2). About 24% of respondents suggested independently that images needed more labeling to help with orientation and identification. This first phase of supplying a comprehensive imaging library can be regarded as a success. Increasing availability and incorporating dynamic labeling are well recognized as important design concepts for electronic learning resources and these will be improved in the second phase of delivery as a direct result of student feedback. Hopefully other centers can benefit from this experience and will consider such a venture to be worthwhile.

Angiopoietin and Tie signaling pathways in vascular development.

The angiopoietin ligands and Tie receptors belong to a novel class of ligand/receptor families, which play critical roles in blood vessel formation. They are considered to control numerous signaling pathways that are involved in diverse cellular processes, such as cell migration, proliferation and survival, and reorganization of the actin cytoskeleton. In this review, we summarize the important biochemical and biological properties of this interesting ligand/receptor family. Particular emphasis will be made on potential downstream targets and consequences of the endothelial cell behavior, due to regulation by the angiopoietin/Tie pathway.

A molecular and genetic analysis of renalglomerular capillary development.

The adult kidney is highly vascular and receives about 20% of the cardiac output, yet the mode of development of the glomerular capillaries is not fully understood. At the inception of nephrogenesis the condensed metanephric mesenchyme contains no patent capillaries. However, in this current study we detected vascular endothelial growth factor (VEGF) mRNA and protein in uninduced mouse E11 metanephric mesenchyme and in cell lines from this tissue. Moreover, transcripts for receptor tyrosine kinases which are markers of endothelial precursors (VEGFR-1/Flt-1, VEGFR-2/Flk-1 and Tie-1) were expressed by the E11 mesenchyme. In transgenic mice, Tie1/LacZ-expressing cells were identified in E11 renal mesenchyme when patent vessels were absent. Moreover, a similar pattern of transgene expression was detected within intermediate mesoderm condensing to form metanephric mesenchyme. When Tie-1/LacZ E11 metanephroi were transplanted into the nephrogenic cortex of wild-type mice, transgene-expressing capillary loops were detected in glomeruli developing in donor tissue. In contrast, glomerular Tie-1/LacZ-positive vessels never developed in rudiments in organ culture. We postulate that endothelial precursors are present at the inception of the mouse nephrogenesis, and these differentiate and undergo morphogenesis into glomerular capillaries when experimental conditions resemble those found in the metanephros in vivo.

A combinatorial role of angiopoietin-1 and orphan receptor TIE1 pathways in establishing vascular polarity during angiogenesis.

Vascular polarity is a fundamental feature of angiogenesis and left-right asymmetry of the vascular network. Contrary to this importance, the molecular basis of vascular polarity is completely unknown. In this report, we show that the combinatorial function of angiopoietin-1 and the orphan receptor TIE1 is critical specifically for the development of the right-hand side venous system but is dispensable for the left-hand side venous system. Furthermore, our current finding reveals the existence of a distinct genetic program for the establishment of the right-hand side and left-hand side vascular networks well before the network asymmetry becomes morphologically discernible.

Molecular analysis of the expression of transthyretin in intestine and liver from trisomy 18 fetuses.

Human trisomy 18 (Edwards syndrome) provides a model for the role that genes on chromosome 18 play in fetal development. Trisomy 18 occurs in approximately 1 in 3000 live births. Despite its compatibility with life in 5% of cases, prolonged survival is rare. Anomalies involve the urogenital, cardiac, craniofacial and central nervous systems. The abnormalities could be caused by the abnormal expression of developmentally important genes on chromosome 18. We have investigated the quantity and localisation of the expression of a candidate gene, transthyretin (TTR), on chromosome 18 at the RNA level in intestine and liver tissues from trisomic fetuses and have compared the expression with normal age-matched fetal tissues. The mRNA level of TTR in 10 to 14-week intestine was the same in trisomy 18 and control tissues. However, overexpression was seen for both trisomy 18 liver and intestine at 20-23 weeks. TTR transports both thyroxine and retinol and is therefore important for normal fetal development.

Origin of glomerular capillaries: is the verdict in?

Classical studies with murine embryonic kidneys (metanephroi) grown in organ culture or on the avian chorio-allantoic membrane have suggested that kidney endothelia arise by ingrowth or angiogenesis. More recent studies, however, indicate that glomerular capillaries and arterioles may form in situ by vasculogenesis when more realistic experimental conditions are deployed: these include glomerulogenesis after transplantation of metanephroi to the nephrogenic renal cortex of mice as well as development in oculo. This conclusion is supported by the finding that receptor tyrosine kinases such as VEGFR-1/2 and Tie-1, characteristic of endothelial precursors, are expressed in the metanephros at a stage when no patent vessels are apparent. Further studies are required to determine the origin of endothelial cells in renal vessels of larger calibre.

Effects of oxygen on vascular patterning in Tie1/LacZ metanephric kidneys in vitro.

Tie1 is an endothelial lineage-specific receptor. Using Tie1/LacZ mice we previously demonstrated in situ differentiation of glomerular capillaries after transplantation of renal precursors into the neonatal nephrogenic kidney cortex. We now report studies with Tie1/LacZ metanephric kidneys explanted in vitro at a stage when Tie1/LacZ-expressing cells surround nephron precursors but glomeruli are unformed. After 4 days of serum-free organ culture in 21% O2, transgene-expressing vessels regressed. In contrast, in 3% O2, transgene was expressed between epithelial tubules by cellular masses containing poorly defined lumens. The normal branching of Tie1/LacZ-expressing vessels which occurred in vivo was absent in vitro and glomeruli forming in culture lacked capillaries. Similar observations were made in wild-type metanephroi using vascular endothelial growth factor receptor 2 (Flk1) as an endothelial marker. We speculate that the metanephros is hypoxic in vivo to permit endothelial growth but other cues must be required for construction of the microcirculation since hypoxia failed to elicit normal patterning in vitro.

Overexpression of esterase D in kidney from trisomy 13 fetuses.

Human trisomy 13 (Patau syndrome) occurs in approximately 1 in 5,000 live births. It is compatible with life, but prolonged survival is rare. Anomalies often involve the urogenital, cardiac, craniofacial, and central nervous systems. It is possible that these abnormalities may be due to the overexpression of developmentally important genes on chromosome 13. The expression of esterase D (localized to chromosome 13q14.11) has been investigated in both muscle and kidney from trisomy 13 fetuses and has been compared with normal age- and sex-matched fetal tissues, by using northern analysis. More than a twofold increase in expression of esterase D was found in the kidney of two trisomy 13 fetuses, with normal levels in a third. Overexpression was not seen in the muscle tissues from these fetuses.

Early embryonic failure associated with uniparental disomy for human chromosome 21.

As many as 16% of all recognized pregnancies may be anembryonic, with failure of the embryo at a very early stage of development leaving only the extraembryonic components of the conceptus to proliferate. Studies in the mouse have shown that the maternal and paternal contributions to the genome of the zygote are not functionally equivalent, due to parental genomic imprinting. Uniparental disomy can reveal imprinting effects, as in this phenomenon both members of a chromosome pair are inherited from the same parent. We have carried out a systematic search for uniparental disomy in tissues from 23 cases of early embryonic failure, using variable number tandem repeat (VNTR) analysis and PCR amplification of polymorphic short sequence repeats. Two cases of maternal uniparental heterodisomy for chromosome 21 were identified. One case occurred in conjunction with trisomy for chromosomes 7 and 9, but in the other case maternal uniparental heterodisomy for chromosome 21 was the only chromosomal abnormality found. We therefore postulate that there may be developmentally important genes on human chromosome 21 which are imprinted such that both parental copies are essential for normal embryogenesis.

Linkage analysis of 62 X-chromosomal loci excludes the X chromosome in an Icelandic family showing apparent X-linked recessive inheritance of neural tube defects.

We report here the findings of a linkage analysis, involving numerous markers from the human X chromosome, in an attempt to localise a putative gene causing apparent X-linked spina bifida and anencephaly (SBA) in a large Icelandic pedigree. Two-point linkage analysis was performed using markers from 62 informative loci in this family. Although small positive lod scores were found at a number of these loci, none reached the significance level for linkage. Haplotypes were extensively analysed and found to exclude linkage to the X chromosome.

Universal GFP reporter for the study of vascular development.

We report the generation and characterization of transgenic mouse and zebrafish expressing green fluorescent protein (GFP) specifically in vascular endothelial cells in a relatively uniform fashion. These reporter lines exhibit fluorescent vessels in developing embryos and throughout adulthood, allowing visualization of the general vascular patterns with single cell resolution. Furthermore, we show the ability to purify endothelial cells from whole embryos and adult organs by a single step fluorescence activated cell sorting. We expect that these transgenic reporters will be useful tools for imaging vascular morphogenesis, global gene expression profile analysis of endothelial cells, and high throughput screening for vascular mutations.