No increased risk of psychological/behavioral disorders in siblings of women with hyperemesis gravidarum (HG) unless their mother had HG.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, is characterized by prolonged maternal stress, undernutrition and dehydration. Maternal stress and malnutrition of pregnancy are linked to poor neonatal outcome and associated with poor adult health, and we recently showed that in utero exposure to HG may lead to increased risks of psychological and behavioral disorders in the offspring. In addition, we have shown familial aggregation of HG, which is strong evidence for a genetic component to the disease. In this study, we compare the rates of psychological and behavioral disorders in 172 adults with and 101 adults without a sibling with HG. The rate of emotional/behavioral disorders is identical (15%) in both groups. The results suggest that the etiology of HG is not likely to include genetic factors associated with emotional and behavioral disorders. In addition, this study provides evidence that the increased incidence of psychological/behavioral disorders among offspring of women with HG is attributable to the HG pregnancy itself, rather than to confounding genetic factors linked to HG.

Prenatal exposure to hyperemesis gravidarum linked to increased risk of psychological and behavioral disorders in adulthood.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, is characterized by long-term maternal stress, undernutrition and dehydration. While maternal stress and malnutrition of pregnancy are linked to poor neonatal outcome and associated with poor adult health, long-term outcome of fetal exposure to HG has never been explored. The purpose of this study is to determine whether long-term emotional and behavioral diagnoses may be associated with fetal exposure to HG. Emotional and behavioral diagnoses of adults born of a pregnancy complicated by HG were compared to diagnoses from non-exposed controls. Offspring exposed to HG in utero were significantly more likely to have a psychological and behavioral disorder (OR = 3.6, P < 0.0001) with diagnoses primarily of depression, bipolar disorder and anxiety. In utero exposure to HG may lead to increased risks of psychological and behavioral disorders in the offspring.

The psychosocial burden of hyperemesis gravidarum.

OBJECTIVE: To describe the psychosocial burden of hyperemesis gravidarum (HG) in a large cohort of affected women, focusing on previously unreported problems. STUDY DESIGN: Women with HG described their pregnancy history in an open-ended survey administered internationally through an HG website during 2003 to 2005. RESULT: Of the 808 participants, 626 (77.5%) were American. A large majority (82.8%) reported that HG caused negative psychosocial changes, consisting of (1) socioeconomic changes, for example, job loss or difficulties, (2) attitude changes including fear regarding future pregnancies and (3) psychiatric sequelae, for example, feelings of depression and anxiety, which for some continued postpartum. Women who reported that their health-care provider was uncaring or unaware of the severity of their symptoms were nearly twice as likely to report these psychiatric sequelae (odds ratio 1.86, 95% confidence interval 1.06 to 3.29, P=0.032). CONCLUSION: Over 80% of a large cohort of women with HG reported that HG caused a negative psychosocial impact.

The hD52 (TPD52) gene is a candidate target gene for events resulting in increased 8q21 copy number in human breast carcinoma.

Chromosome band 8q21 is frequently overrepresented in human cancer, but to date no 8q21 target gene has been proposed. The hD52 (TPD52) gene is of potential significance in breast and other cancers due to its location and expression pattern. Fine mapping of hD52 placed this locus within the peak of the 8q21 amplicon delineated in the SK-BR-3 breast carcinoma cell line, and a positive association between hD52 gene dosage and transcript levels was subsequently demonstrated in four breast carcinoma cell lines, including SK-BR-3. Increased copy number (ICN) was measured using Southern blot analyses in 3/32 human breast carcinomas at hD52, and the related hD54 gene in 20q13.2-q13.3. Subsequent immunohistochemical analysis of hD52 expression in 19 breast carcinomas with varying hD52 gene dosages demonstrated a significant positive association between hD52 dosage and hD52 expression using a Spearman rank correlation coefficient (r(s) = 0.573, alpha = 0.01) and a Wilcoxon rank-sum test (alpha = 0.05). On the basis of its map location and expression pattern in breast carcinoma, we therefore propose hD52 as a candidate target gene at chromosome band 8q21.

Characterization of genes encoding known and novel human mast cell tryptases on chromosome 16p13.3.

Tryptases are serine proteases implicated in asthma and are very highly expressed in human mast cells. They fall into two groups, alpha and beta. Although several related tryptase mRNAs are known, it is unclear which if any are transcripts of separate haploid genes. The studies described here investigated the nature and number of human tryptases and sought possibly novel members of the family. To this end, two human bacterial artificial chromosome (BAC) clones containing tryptase genes were identified and mapped to chromosome 16p13.3, of which approximately 2.2 megabases are syntenic with the part of mouse chromosome 17 containing tryptase genes mouse mast cell protease (mMCP)-6 and -7. Sequencing and restriction mapping suggest that the BACs may partially overlap. Sequenced BAC genes correspond to three known beta-tryptases (betaI, betaII, and betaIII), an alpha-like gene, and a pair of novel hybrid genes related partly to alpha/beta-tryptases and partly to orthologs of mMCP-7. betaII and betaIII, betaI and alphaII, as well as the two mMCP-7-like genes, may be alleles at single loci; in total, there are at least three nonallelic tryptase genes in the isolated BAC clones. DNA blotting and restriction analysis suggest that the BACs include most members of the immediate tryptase family. Thus, chromosome 16p13.3 harbors a cluster of known and previously undescribed members of the tryptase gene family.

Molecular cytogenetic analysis of consistent abnormalities at 8q12-q22 in breast cancer.

Studies using comparative genomic hybridization (CGH) indicate that portions of chromosome arm 8q from 8q12 to 8qter are present at an increased relative copy number in a broad range of solid tumors. In this study we define an approximately 1 Mb wide region that appears to be frequently abnormal in copy number or structure in breast cancer cell lines and primary tumors. This was accomplished by fluorescence in situ hybridization (FISH) with yeast artificial chromosomes (YACs) mapped to 8q2-q22. Eleven breast cancer cell lines and ten primary tumors were analyzed. A minimal region of rearrangement was localized to the CEPH-YAC 928F9 in three breast cancer cell lines with unbalanced translocation breakpoints mapping in this region. Unbalanced translocations also were detected in two primary tumors mapping between CEPH-YAC clones 890C4 and 936B3, flanking 928F9. An increased copy number in the minimal region was detected in nine cell lines and in multiple primary tumors. This suggests the possibility that a single gene mapping to 928F9 is involved in breast cancer development or progression and may be deregulated by copy number increases in some tumors and by translocation in others. Four expressed sequence tags were mapped to YAC 928F9 and analyzed for rearrangements by Southern analysis and for abnormal expression by Northern analysis.

Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains.

Lipomas are one of the most common mesenchymal neoplasms in humans. They are characterized by consistent cytogenetic aberrations involving chromosome 12 in bands q14-15. Interestingly, this region is also the site of rearrangement for other mesenchymally derived tumors. This study demonstrates that HMGI-C, an architectural factor that functions in transcriptional regulation, has been disrupted by rearrangement at the 12q14-15 chromosomal breakpoint in lipomas. Chimeric transcripts were isolated from two lipomas in which HMGI-C DNA-binding domains (AT hook motifs) are fused to either a LIM or an acidic transactivation domain. These results, identifying a gene rearranged in a benign neoplastic process that does not proceed to a malignancy, suggest a role for HMGI-C in adipogenesis and mesenchyme differentiation.

Identification of a YAC spanning the translocation breakpoints in uterine leiomyomata, pulmonary chondroid hamartoma, and lipoma: physical mapping of the 12q14-q15 breakpoint region in uterine leiomyomata.

Uterine leiomyomata are the most common tumors in women and can cause abnormal uterine bleeding, pelvic pain, and infertility. Approximately 200,000 hysterectomies are performed annually in the U.S. to relieve patients of the medical sequelae of these benign neoplasms. Our efforts have focused on cloning the t(12;14)(q14-q15;q23-q24) breakpoint in uterine leiomyoma to further our understanding of the biology of these tumors. Thirty-nine YACs and six cosmids mapping to 12q14-q15 have been mapped by fluorescence in situ hybridization to tumor metaphase chromosomes containing a t(12;14). One YAC spanned the translocation breakpoint and was mapped to tumor metaphases from a pulmonary chondroid hamartoma containing a t(12;14)(q14-q15;q23-q24) and a lipoma containing a t(12;15)(q15;q24); this YAC also spanned the breakpoint in these two tumors, suggesting that the same gene on chromosome 12 may be involved in the pathobiology of these distinct benign neoplasms.