Germline gain-of-function mutations in SOS1 cause Noonan syndrome.

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice.

Adenomatous polyposis coli (APC) is required for normal development of skin and thymus.

The tumor suppressor gene Apc (adenomatous polyposis coli) is a member of the Wnt signaling pathway that is involved in development and tumorigenesis. Heterozygous knockout mice for Apc have a tumor predisposition phenotype and homozygosity leads to embryonic lethality. To understand the role of Apc in development we generated a floxed allele.

A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response.

The Chk2-p53-PUMA pathway is a major regulator of DNA-damage-induced apoptosis in response to double-strand breaks in vivo. Through analysis of 53BP1 complexes we have discovered a new ubiquitin protease, USP28, which regulates this pathway. Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA damage.

Dissecting cancer pathways and vulnerabilities with RNAi.

The latest generation of molecular-targeted cancer therapeutics has bolstered the notion that a better understanding of the networks governing cancer pathogenesis can be translated into substantial clinical benefits. However, functional annotation exists for only a small proportion of genes in the human genome, raising the likelihood that many cancer-relevant genes and potential drug targets await identification. Unbiased genetic screens in invertebrate organisms have provided substantial insights into signaling networks underlying many cellular and organismal processes.

COMT genotype and manic symptoms in schizophrenia.

Inconsistencies in the relation between COMT variation and schizophrenia may be clarified by careful delineation of a target phenotype. The present study reports a significant association between a COMT haplotype and the severity of manic symptoms in 162 patients with schizophrenia or schizoaffective disorder (SZ). These data suggest that the effect of COMT variation may be associated with comorbid manic symptoms in SZ.

Inactivation of conditional Rb by Villin-Cre leads to aggressive tumors outside the gastrointestinal tract.

We have crossed mice carrying the conditional Rb(tm2Brn) allele with a constitutive Villin-Cre transgenic mouse. The Villin promoter in these animals is highly expressed in adult intestine and kidney proximal tubules and is expressed in the gut and nephros anlagen during embryogenesis. We report here that these mice develop tumors between 12 and 17 months old outside the gastrointestinal (GI) tract.

COMT genetic variation confers risk for psychotic and affective disorders: a case control study.

Background: Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls.

Comparative analysis of algorithms for identifying amplifications and deletions in array CGH data.

Motivation: Array Comparative Genomic Hybridization (CGH) can reveal chromosomal aberrations in the genomic DNA. These amplifications and deletions at the DNA level are important in the pathogenesis of cancer and other diseases. While a large number of approaches have been proposed for analyzing the large array CGH datasets, the relative merits of these methods in practice are not clear.

A genetic screen for candidate tumor suppressors identifies REST.

Tumorigenesis is a multistep process characterized by a myriad of genetic and epigenetic alterations. Identifying the causal perturbations that confer malignant transformation is a central goal in cancer biology. Here we report an RNAi-based genetic screen for genes that suppress transformation of human mammary epithelial cells.

Comparison of pooled fresh frozen serum to proficiency testing material in College of American Pathologists surveys: cortisol and immunoglobulin E.

Context: The College of American Pathologists (CAP) provides proficiency testing (PT) surveys to laboratories around the world.

Objectives: To compare diagnostic assay methods for serum/plasma cortisol and immunoglobulin (Ig) E in terms of their bias and precision, to determine how well CAP PT specimens simulate human serum, and to reassess proficiency test grading criteria in light of these findings.

Design: A participant-blinded, prospective trial.

MAGIC, an in vivo genetic method for the rapid construction of recombinant DNA molecules.

We describe a highly engineered in vivo cloning method, mating-assisted genetically integrated cloning (MAGIC), that facilitates the rapid construction of recombinant DNA molecules. MAGIC uses bacterial mating, in vivo site-specific endonuclease cleavage and homologous recombination to catalyze the transfer of a DNA fragment between a donor vector in one bacterial strain and a recipient plasmid in a separate bacterial strain. Recombination events are genetically selected and result in placement of the gene of interest under the control of new regulatory elements with high efficiency.

Improving identification of differentially expressed genes in microarray studies using information from public databases.

We demonstrate that the process of identifying differentially expressed genes in microarray studies with small sample sizes can be substantially improved by extracting information from a large number of datasets accumulated in public databases. The improvement comes from more reliable estimates of gene-specific variances based on other datasets. For a two-group comparison with two arrays in each group, for example, the result of our method was comparable to that of a t-test analysis with five samples in each group or to that of a regularized t-test analysis with three samples in each group.

Integration of genetics into clinical teaching in medical school education.

Medical genetics has moved from the study of rare conditions to the illumination of disorders that impact the entire spectrum of medical practice. While there have been a number of predictions and concerns about this impact, this article examines three areas where medical genetics is clearly an important tool in medical practice. First, a family history aids in risk assessment, even in common disorders that are multifactorial.

Genetics in medical practice.

Medical genetics has been formally recognized as a medical specialty in the United States only within the past decade. Initially, medical genetics was concerned with relatively rare single gene or chromosomal disorders, but with the sequencing of the human genome, genetics has become the driving force in medical research and is now poised for integration into medical practice. This article offers a perspective on the role of genetics in medical practice and how this role may evolve over the next several years.

Determination of end points for treatment of neurofibromatosis 1.

Neurofibromatosis 1 is a progressive disorder that affects multiple systems of the body. Management is currently focused on anticipatory guidance, genetic counseling, and symptomatic treatment of specific lesions, usually through surgery. Insights into pathogenesis of the disorder are beginning to suggest possible mechanisms of treatment, and clinical trials have begun for some types of lesions.

Clinical features and pathobiology of neurofibromatosis 1.

Neurofibromatosis 1 is a progressive multisystem disorder. The hallmark feature is the occurrence of nerve sheath tumors, neurofibromas. Other features include tumors such as optic gliomas and malignant peripheral nerve sheath tumors.

Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression.

Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements. Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract. Using gene knockout approaches, we introduced a null mutation into murine Fen1.