The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.

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Remodelling the extracellular matrix in development and disease.

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

http://enigma.ini.usc.edu/wp-content/uploads/2010/04/Effect-of-COMT-Val108-158-Met-genotype-on-frontal-lobe-function-and-risk-for-schizophrenia.pdf

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

Mutational processes of simple sequence repeats (SSRs) in complex genomes are poorly understood. We examined these processes by introducing a two-phase mutation model. In this model, most mutations are single-step changes, but infrequent large jumps in repeat number also occur. We used computer simulations to determine expected values of statistics that reflect frequency distributions of allele size for the two-phase model and two alternatives, the one-step and geometric models. The theoretical expectations for each model were tested by comparison with observed values for 10 SSR loci genotyped in the Sardinian population, whose genetic and demographic histories have been previously reconstructed. The two-phase model provided the best fit to the data for most of these loci in this population. In the analysis we assumed that the loci were neutral and that this population had undergone rapid population growth. Recent observations made for unstable trinucleotide repeats support our suggestion that frequent small changes and rare large changes in repeat number represent two distinct classes of mutation at SSR loci. We genotyped the same 10 loci in Egyptian and sub-Saharan African samples to assess the utility of SSRs for studying the divergence of populations and found that estimates of interpopulation distances from SSRs were similar to those derived from analysis of mitochondrial DNA.

https://www.pnas.org/content/pnas/91/8/3166.full.pdf

Mutational processes of simple-sequence repeat loci in human populations.

Holoprosencephaly (HPE) is a common developmental defect of the forebrain and frequently the midface in humans, with both genetic and environmental causes HPE has a prevalence of 1:250 during embryogenesis and 1:16,000 newborn infants, and involves incomplete development and septation of midline structures in the central nervous system (CNS) with a broad spectrum of clinical severity Alobar HPE, the most severe form which is usually incompatible with postnatal life, involves complete failure of division of the forebrain into right and left hemispheres and is characteristically associated with facial anomalies including cyclopia, a primitive nasal structure (proboscis) and/or midfacial clefting At the mild end of the spectrum, findings may include microcephaly, mild hypotelorism, single maxillary central incisor and other defects (Fig 1) This phenotypic variability also occurs between affected members of the same family The molecular basis underlying HPE is not known, although teratogens, non-random chromosomal anomalies and familial forms with autosomal dominant and recessive inheritance have been described HPE3 on chromosome 7q36 is one of at least four different loci implicated in HPE Here, we report the identification of human Sonic Hedgehog (SHH) as HPE3-the first known gene to cause HPE Analyzing 30 autosomal dominant HPE (ADHPE) families, we found five families that segregate different heterozygous SHH mutations Two of these mutations predict premature termination of the SHH protein, whereas the others alter highly conserved residues in the vicinity of the alpha-helix-1 motif or signal cleavage site

Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.

We introduce a new genetic distance for microsatellite loci, incorporating features of the stepwise mutation model, and test its performance on microsatellite polymorphisms in humans, chimpanzees, and gorillas. We find that it performs well in determining the relations among the primates, but less well than other distance measures (not based on the stepwise mutation model) in determining the relations among closely related human populations. However, the deepest split in the human phylogeny seems to be accurately reconstructed by the new distance and separates African and non-African populations. The new distance is independent of population size and therefore allows direct estimation of divergence times if the mutation rate is known. Based on 30 microsatellite polymorphisms and a recently reported average mutation rate of 5.6 x 10(-4) at 15 dinucleotide microsatellites, we estimate that the deepest split in the human phylogeny occurred about 156,000 years ago. Unlike most previous estimates, ours requires no external calibration of the rate of molecular evolution. We can use such calibrations, however, to test our estimate.

https://www.pnas.org/content/pnas/92/15/6723.full.pdf

Genetic absolute dating based on microsatellites and the origin of modern humans.

Forty-nine individuals have been identified with deletions or translocations involving the short arm of chromosome 5. While most display the classical phenotype of the cri-du-chat syndrome, several of the patients do not have the syndrome or have only a subset of the clinical features. Somatic cell hybrids containing the deleted chromosome 5 were derived from each patient. Each somatic cell hybrid was analyzed at the DNA level using 136 chromosome 5p-specific DNA fragments. It was possible to unambiguously order most of the chromosomal breakpoints present in the somatic cell hybrids based on the hybridization patterns of Southern blots. Further comparisons between the deletions present in the patients and their clinical features identified several chromosomal regions that were involved in specific clinical features. A critical chromosomal region involved the high-pitched cry mapped to 5p15.3, while the chromosomal region involved in the remaining features of the cri-du-chat syndrome mapped to a small region within 5p15.2. Deletions that did not include these two chromosomal regions presented varying clinical phenotypes from severe mental retardation and microcephaly to a clinically normal phenotype. These results demonstrate the need for careful characterization of a 5p deletion in prenatal cases before clinical predictions are made.

Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome

A Microsatellite Genetic Linkage Map of Human Chromosome 18

Holoprosencephaly (HPE) is a common developmental defect that results in a spectrum of craniofacial malformations. HPE is genetically heterogeneous, some cases being associated with deletions of the short arm of chromosome 18. In order to map the putative HPE gene located on 18p (HPE4) more precisely, six patients with various cytogenetic 18p deletions and clinical features of HPE have been characterized by using a combination of somatic cell hybrid analysis and FISH. By using a set of 27 chromosome 18p-specific markers, the deletion in each patient was characterized. The HPE minimal critical region on 18p was defined on a molecular level, localizing the HPE4 gene to 18p11.3.

Physical mapping of the holoprosencephaly critical region in 18p11.3.

Seven individuals with deletions of the distal long arm of chromosome 18 were evaluated at the clinical, cytogenetic, and molecular levels. The patients had varying degrees of typical clinical findings associated with the 18q- syndrome. Cytogenetic analysis revealed deletions from 18q21.3 or 18q22.2 to qter. Somatic cell hybrids derived from the patients were molecularly characterized using ordered groups of probes isolated from a chromosome 18-specific library. In general, the size of the deletion could be correlated with the severity of the phenotype. Based on the clinical pictures of these seven patients, a preliminary phenotypic map for the clinical features associated with deletions of the distal portion of the long arm has been generated. Furthermore, genes previously localized to 18q21 were mapped relative to the chromosome breakpoints present in these patients.

Molecular analysis of the 18q- syndrome--and correlation with phenotype

The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively.

Katherine Rojas

Papers

Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome

A Microsatellite Genetic Linkage Map of Human Chromosome 18

Physical mapping of the holoprosencephaly critical region in 18p11.3.

Molecular analysis of the 18q- syndrome--and correlation with phenotype

The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively.