[Genotype-phenotype analysis of Fabry disease caused by GLA gene variation in a pedigree].

Objective: To investigate the clinical phenotype and genetic characteristics of patients with Fabry disease caused by a GLA variant, IVS4+919G>A. Methods: It was a prospective study. Fabry disease screening was conducted among high-risk population in Ninghai from October 2021 to August 2023. Those children with decreased α-galactosidase enzyme activity<2.40 µmol/(L·h) or elavated Lyso-GL-3 level>1.10 µg/L in dried blood spot (DBS) method underwent GLA genetic testing for diagnosis confirmation. Meanwhile, family screening was carried out. A proband and his family members diagnosed with Fabry disease were research subjects. The clinical and genetic characteristics of patients with Fabry disease caused by the GLA variant (IVS4+919G>A) were analyzed. Results: The female proband aged 9.8 years with pain in both lower limbs as the initial symptom was found to have a heterozygous GLA variant IVS4+919G>A among 102 patients. In family screening, there were 4 family members (proband's father, elder sister, elder male cousin and elder female cousin) with Fabry disease and a family member (proband's fifth aunt) with a GLA variant. Among these 4 diagnosed family members, the elder male cousin of the proband, a boy aged 13.2 years had a heterozygous GLA variant, IVS4+919G>A with intermittent pain in both lower limbs as the initial symptom. The proband's father had knee joint pain. The proband's elder sister had decreased vision and his elder female cousin had no obvious symptoms. The proband's fifth aunt with a GLA variant had decreased vision. Conclusions: High-risk screening in children and family screening are helpful for early diagnosis and treatment of Fabry disease. Neuropathic pain may be a early symptom in children with Fabry disease caused by the GLA variant, IVS4+919G>A.

The effect of BMP2/Smads pathway mediating platelet-rich fibrin on rat bone mesenchymal stem cells.

OBJECTIVE: We explored the influences on platelet-rich fibrin (PRF) to rat Bone Mesenchymal Stem Cells (BMSCs), as well as the role of bone morphogenetic protein 2 (BMP2)/maternal signal protein homolog (Smads) pathway. MATERIALS AND METHODS: The proposed research is approved by the ethics board of the Second Affiliated Hospital of Harbin Medical University. The BMSCs were isolated and purified. The BMSCs were assigned to a control group arbitrarily, PRF group, BMP activator group and BMP inhibitor group (hereinafter referred to as activator group and inhibitor group). Each group of BMSCs in the logarithmic growth phase was detected for the alkaline phosphatase (ALP) activity since 3 days and 14 days of culture; CCK-8 assay was conducted for detection of the proliferation of BMSCs; Real time PCR was conducted for detection of the osteogenic differentiation marker collagen I (COL-I), BMP2, Runt-related transcription factor 2(RUNX2), osteocalcin (OCN) mRNA relative expression levels; Western-Blot detection of BMP2, OCN, P-SMAD1/5/8, relative expression level of RUNX2 protein. RESULTS: In contrast to the control group, BMSCs' the ALP activity of the PRF group, activator group, as well as inhibitor group increased for 3 days and 14 days, and the activator group>PRF group>inhibitor group (p≤0.05). ALP activity in each group was elevated with the increase in culture time, the ALP activity of the control group, PRF group, activator group and inhibitor group increased (p≤0.05). In comparison to the control group, the relevant expression levels of COL-I, BMP-2, RUNX2 and OCN in the PRF group, activator group, and inhibitor group increased, and the activator group>PRF group>inhibitor group (p≤0.05). The relative expression levels of BMP2, OCN, p-SMAD1/5/8 and RUNX2 protein in each group were statistically different, the activator group>PRF group>control group>inhibitor group (p≤0.05). CONCLUSIONS: PRF can promote the proliferation and osteogenic differentiation of BMSCs by activating the BMP2/Smads signaling pathway.

Identification of a novel cancer microbiome signature for predicting prognosis of human breast cancer patients.

BACKGROUND: Prognosis of breast cancer (BC) patients differs considerably and identifying reliable prognostic biomarker(s) is imperative. With evidence that the microbiome plays a critical role in the response to cancer therapies, we aimed to identify a cancer microbiome signature for predicting the prognosis of BC patients. METHODS: The TCGA BC microbiome data (TCGA-BRCA-microbiome) was downloaded from cBioPortal. Univariate and multivariate Cox regression analyses were used to examine association of microbial abundance with overall survival (OS) and to identify a microbial signature for creating a prognostic scoring model. The performance of the scoring model was assessed by the area under the ROC curve (AUC). Nomograms using the microbial signature, clinical factors, and molecular subtypes were established to predict OS and progression-free survival (PFS). RESULTS: Among 1406 genera, the abundances of 94 genera were significantly associated with BC patient OS in TCGA-BRCA-microbiome dataset. From that set we identified a 15-microbe prognostic signature and developed a 15-microbial abundance prognostic scoring (MAPS) model. Patients in low-risk group significantly prolong OS and PFS as compared to those in high-risk group. The time-dependent ROC curves with MAPS showed good predictive efficacy both in OS and PFS. Moreover, MAPS is an independent prognostic factor for OS and PFS over clinical factors and PAM50-based molecular subtypes and superior to the previously published 12-gene signature. The integration of MAPS into nomograms significantly improved prognosis prediction. CONCLUSION: MAPS was successfully established to have independent prognostic value, and our study provides a new avenue for developing prognostic biomarkers by microbiome profiling.

[Clinical features and enzyme replacement therapy in 4 children with Fabry disease].

Objective: To analyze the clinical features and efficacy of enzyme replacement therapy in 4 children with Fabry disease. Methods: A retrospective analysis of the clinical manifestations, laboratory findings, genetic variations and treatment were conducted in 4 children with Fabry disease in Children's Hospital of Zhejiang University School of Medicine from January 2014 to July 2020. Results: All four children (2 males, 2 females) with onset age of 12.4 (6.0-16.8) years were diagnosed based on clinical features, α-Gal A enzyme activity, genetic analysis and family history. The clinical manifestations varied in 4 children. All patients had left ventricular hypertrophy and abnormal urinalysis results, 1 case of neuropathic pain, 2 cases of hypohidrosis, 1 case of insipidus, but no angiokeratomas or hearing abnormalities were found. Three missense mutations of GLA gene were identified: c.424T>C (p.C142R), C.335G>A (p.R112H) and c.644A>G (p.N215S). The first two gene mutations were classical phenotypes, and the last one had also been reported in a classic case. In Case 1, no severe adverse events were reported in the first two months of agalsidase beta treatment. The dosage was 1 mg/kg once every 2 weeks. Symptoms of pain intensity and hypohidrosis were improved. Transiently elevated proteinuria was observed but it returned to normal after a week without any treatment. Conclusions: Clinical manifestations of Fabry disease varied in childhood. Multidisciplinary collaboration is required for its early diagnosis and treatment. Severe adverse events are rare in children with short-term therapy of agalsidase beta.

[Optimized AAV package and experimental application of recombinant AAV8/hFâ § for gene therapy on hemophilia A mice].

Objective: To evaluate the effects of adeno-associated virus (AAV) carrying hFⅧ by serotype 8 (AAV8/hFⅧ) on hemophilia A (HA) mice by gene therapy strategy. Methods: pAAV-CB-EGFP, pH22 (serotype 2) and pfΔ6 (adenovirus helper) were used to package AAV into HEK-293 cells in different conditions (ratios of cells to plasmids). The efficiency of transfection and infection were evaluated using immunofluorescence microscope to seek an optimized package condition. pAAV-TTR-hFⅧ, pH 28 (serotype 8) and pfΔ6 were applied to package AAV8/hFⅧ in HEK-293 cells using the optimized package condition. The purified AAV8/hFⅧ were intravenously injected into HA mice and the effects of gene therapy were estimated. Results: The efficiency of package was evaluated according to the amount and intensity of enhanced green fluorescent protein (EGFP) under immunofluorescence microscope. Four package conditions including 10 cm-dish to transfect 10 µg plasmids, 20 cm-dish to 20 µg, 30 µg and 40 µg plasmids were employed, and the condition of 20 cm-dish to transfect 20 µg plasmids reached the highest transfection efficiency at 24 h, 48 h and 72 h after transfection. The small scale AAV-EGFP was packaged using the optimized condition and an AAV crude extract was harvested by a freeze-thaw method. HEK-293 and 16095 cells were infected by the AAV crude extract, and the preferential infection efficiency was recognized in 16095 cells under immunofluorescence microscope. Then, AAV8/hFⅧ was packaged and purified based on the optimized transfection condition, and the high purity of AAV8/hFⅧ was detected by Western blot. Fractions of AAV8/hFⅧ at the dose of 8×10(12) vg/kg were injected into HA mice through tail vein, an eye-bleeding was performed at every two weeks, and the activity of FⅧ was measured by aPTT assay. Results showed that the activity of FⅧ maintained at the therapeutic level and lasted up to 12 weeks after injection. Conclusion: The purified AAV8/hFⅧ based on the optimized package condition could play a role in HA mice gene therapy, and the long-term therapeutic effects of AAV8/hFⅧ were observed in vivo.

[A multicenter study of reference intervals for 15 laboratory parameters in Chinese children].

Objective: To establish comprehensive laboratory reference intervals for Chinese children. Methods: This was a cross-sectional multicenter study. From June 2013 to December 2014, eligible healthy children aged from 6-month to 17-year were enrolled from 20 medical centers with informed consent. They were assessed by physical examination, questionnaire survey and abdominal ultrasound for eligibility. Fasting blood samples were collected and delivered to central laboratory. Measurements of 15 clinical laboratory parameters were performed, including estradiol (E2), testosterone(T), luteinizing hormone(LH), follicle-stimulating hormone(FSH), alanine transaminase(ALT), serum creatinine(Scr), cystatin C, immunoglobulin A(IgA), immunoglobulin G(IgG), immunoglobulin M(IgM), complement (C3, C4), alkaline phosphatase(ALP), uric acid(UA) and creatine kinase(CK). Reference intervals were established according to central 95% confidence intervals for reference population, stratified by age and sex. Results: In total, 2 259 children were enrolled. Finally, 1 648 children were eligible for this study, including 830 boys and 818 girls, at a mean age of 7.4 years. Age- and sex- specific reference intervals have been established for the parameters. Reference intervals of sex hormones increased gradually with age. Concentrations of ALT, cystatin C, ALP and CK were higher in children under 2 years old. Serum levels of sex hormones, creatinine, immunoglobin, CK, ALP and urea increased rapidly in adolescence, with significant sex difference. In addition, reference intervals were variable depending on assay methods. Concentrations of ALT detected by reagents with pyridoxal 5'-phosphate(PLP) were higher than those detected by reagents without PLP. Compared with enzymatic method, Jaffe assay always got higher results of serum creatinine, especially in children younger than 9 years old. Conclusion: This study established age- and sex- specific reference intervals, for 15 clinical laboratory parameters based on defined healthy children.

MicroRNA (miR)-203 and miR-205 expression patterns identify subgroups of prognosis in cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most widespread cancer in humans and its incidence is rising. These tumours can evolve as diseases of poor prognosis, and therefore it is important to identify new markers to better predict its clinical evolution. OBJECTIVES: We aimed to identify the expression pattern of microRNAs (miRNAs or miRs) at different stages of skin cancer progression in a panel of murine skin cancer cell lines. Owing to the increasing importance of miRNAs in the pathogenesis of cancer, we considered the possibility that miRNAs could help to define the prognosis of CSCC and aimed to evaluate the potential use of miR-203 and miR-205 as biomarkers of prognosis in human tumours. METHODS: Seventy-nine human primary CSCCs were collected at the University Hospital of Salamanca in Spain. We identified differential miRNA expression patterns at different stages of CSCC progression in a well-established panel of murine skin cancer cell lines, and then selected miR-205 and miR-203 to evaluate their association with the clinical prognosis and evolution of human CSCC. RESULTS: miR-205 was expressed in tumours with pathological features recognized as indicators of poor prognosis such as desmoplasia, perineural invasion and infiltrative growth pattern. miR-205 was mainly expressed in undifferentiated areas and in the invasion front, and was associated with both local recurrence and the development of general clinical events of poor evolution. miR-205 expression was an independent variable selected to predict events of poor clinical evolution using the multinomial logistic regression model described in this study. In contrast, miR-203 was mainly expressed in tumours exhibiting the characteristics associated with a good prognosis, was mainly present in well-differentiated zones, and rarely expressed in the invasion front. Therefore, the expression and associations of miR-205 and miR-203 were mostly mutually exclusive. Finally, using a logistic biplot we identified three clusters of patients with differential prognosis based on miR-203 and miR-205 expression, and pathological tumour features. CONCLUSIONS: miR-205 and miR-203 tended to exhibit mutually exclusive expression patterns in human CSCC. This work highlights the utility of miR-205 and miR-203 as prognostic markers in CSCC.

Regulating effect of MMP-9 and TIMP-1 in pituitary adenoma invasion.

Pituitary adenomas can cause endocrine disorder and organ damage, with some aggressive ones leading to a high postoperative recurrence rate. The occurrence and development of these type of tumors is closely related with matrix metalloproteinases (MMPs) and endogenous specific tissue inhibitor of MMPs (TIMPs). In this study, the relationship between pituitary adenoma invasion and the changes in MMP-8 and TIMP-1 expressions is analyzed. Specimens from sixty patients with pituitary adenoma were collected in our hospital after surgery, including thirty cases of invasive pituitary adenomas and thirty cases of noninvasive pituitary adenomas. Western blotting and real-time PCR were used to detect MMP-8/TIMP-1 protein and mRNA levels, respectively, in the two types of pituitary adenomas, while ELISA was used to detect both compounds' levels in the patient's serum. Compared with noninvasive pituitary adenomas, MMP-8 was significantly overexpressed in invasive pituitary adenomas, while TIMP-1 was obviously lower (P < 0.05 for both). Moreover, MMP-8 mRNA expression in invasive pituitary adenomas was significantly higher than in noninvasive pituitary adenomas, while TIMP-1 mRNA expression was markedly lower (P < 0.05 for both). Finally, MMP-8 expression in the serum is upregulated in patients with invasive pituitary adenomas relative to the noninvasive ones, and the expression of TIMP-1 significantly reduced (P < 0.05 for both). These results show that increased MMP-8 and decreased TIMP-1 expressions are closely related to the invasive pituitary adenoma, and can be helpful for the evaluation.

A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development.

Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

Hipk2 cooperates with p53 to suppress γ-ray radiation-induced mouse thymic lymphoma.

A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53+/- and p53-/- mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2). More than 30% of radiation-induced tumors from both p53+/- and p53-/- mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by γ-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene.

Presenilin modulates EGFR signaling and cell transformation by regulating the ubiquitin ligase Fbw7.

The epidermal growth factor receptor (EGFR) and Notch signaling pathways have antagonistic roles during epidermal differentiation and carcinogenesis. The molecular mechanisms regulating the crosstalk between EGFR and Notch during epidermal transformation are largely unknown. We found enhanced EGFR-dependent signaling, proliferation and oncogenic transformation caused by loss of presenilins (PS), the catalytic components of gamma-secretase that generates the Notch1 intracellular domain (NICD). The underlying mechanism for abnormal EGFR signaling in PS-deficient cells involves gamma-secretase-independent transcriptional upregulation of the E3 ubiquitin ligase Fbw7. Fbw7alpha, which targets NICD for degradation, regulates positively EGFR by affecting a proteasome-dependent ubiquitination step essential for constitutive degradation and stability of EGFR. To investigate the pathological relevance of this findings in vivo, we generated a novel epidermal conditional PS-deficient (ePS cDKO) mouse by deleting both PS in keratinocytes of the basal layer of the epidermis. The ePS cDKO mice develop epidermal hyperplasia associated with enhanced expression of both EGFR and Fbw7 and reduced NICD levels in keratinocytes. These findings establish a novel role for PS on epidermal growth and transformation by reciprocally regulating the EGFR and Notch signaling pathways through Fbw7.

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis.

There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

Kimura disease: a case report and review of the Chinese literature.

BACKGROUND: Kimura disease, often accompanied by nephrotic syndrome, is a rare, chronic inflammatory disorder of unknown cause. In this report, the clinical and histopathological characteristics of 20 Chinese patients with Kimura disease-associated nephrotic syndrome were retrospectively evaluated. METHODS: We report a case of Kimura disease that was diagnosed recently in our ward, with steroid-responsive but recurrent minimal-change nephrotic syndrome. Meanwhile, we also used three powerful Chinese journal search engines (Cqvip.com, Wanfang.data and ScienceChina) to search the cases reported in Chinese from 1984 to 2007. RESULTS: The nephrotic syndrome of our patient occurred 20 months after the onset of Kimura disease. Renal biopsy revealed minimal-change lesions. The patient was responsive to the steroid, but proteinuria recurred. In most of the 19 other cases, the onset of nephrotic syndrome occurred after subcutaneous masses. Renal biopsy in 13 cases showed mesangial proliferative glomerulonephritis in 9, minimal change disease in 2 and membrane nephropathy in 2 cases. Serum creatinine levels were elevated in 5 patients. CONCLUSION: Normally, Kimura disease-associated nephrotic syndrome patients are sensitive to prednisone therapy but are likely to relapse. In patients with recurrent nephrotic syndrome, renal insufficiency is not uncommon.

Atm heterozygosity does not increase tumor susceptibility to ionizing radiation alone or in a p53 heterozygous background.

Ataxia-Telangiectasia (A-T) is an autosomal recessive human disease characterized by genetic instability, radiosensitivity, immunodeficiency and cancer predisposition, because of mutation in both alleles of the ATM (ataxia-telangiectasia mutated) gene. The role of Atm heterozygosity in cancer susceptibility is controversial, in both human and mouse. Earlier studies identified deletions near the Atm gene on mouse chromosome 9 in radiation-induced lymphomas from p53 heterozygous mice. To determine whether Atm was the target of these deletions, Atm heterozygous as well as Atm/P53 double heterozygous mice were treated with ionizing radiation. There were no significant differences in tumor latency, progression and lifespan after gamma-radiation in Atm heterozygous mice compared with their wild-type control counterparts. Deletions were found on chromosome 9 near the Atm locus in radiation-induced tumors, but in 50% of the cases the deletion included the knockout allele, and the expression of Atm was maintained in the tumors indicating that loss of heterozygosity on chromosome 9 is not driven by Atm, but by an alternative tumor suppressor gene located near Atm on this chromosome. We conclude that Atm heterozygosity does not confer an increase in tumor susceptibility in this context.

Characterization of breast cancer by array comparative genomic hybridization.

Cancer progression is due to the accumulation of recurrent genomic alterations that induce growth advantage and clonal expansion. Most of these genomic changes can be detected using the array comparative genomic hybridization (CGH) technique. The accurate classification of these genomic alterations is expected to have an important impact on translational and basic research. Here we review recent advances in CGH technology used in the characterization of different features of breast cancer. First, we present bioinformatics methods that have been developed for the analysis of CGH arrays; next, we discuss the use of array CGH technology to classify tumor stages and to identify and stratify subgroups of patients with different prognoses and clinical behaviors. We finish our review with a discussion of how CGH arrays are being used to identify oncogenes, tumor suppressor genes, and breast cancer susceptibility genes.

Convergence of congenic mapping and allele-specific alterations in tumors for the resolution of the Skts1 skin tumor susceptibility locus.

Although several familial cancer genes with high-penetrance mutations have been identified, the major genetic component of susceptibility to sporadic cancers is attributable to low-penetrance alleles. These 'weak' tumor susceptibility genes do not segregate as single Mendelian traits and are therefore difficult to find in studies of human populations. Previously, we have proposed that a combination of germline mapping and analysis of allele-specific imbalance in tumors may be used to refine the locations of susceptibility genes using mouse models of cancer. Here, we have used linkage analysis and congenic mouse strains to map the major skin tumor susceptibility locus Skts1 within a genetic interval of 0.9 cM on proximal chromosome 7. This interval lies in an apparent recombination cold spot, and corresponds to a physical distance of about 15 Mb. We therefore, used patterns of allele-specific imbalances in tumors from backcross and congenic mice to refine the location of Skts1. We demonstrate that this single tumor modifier locus has a dramatic effect on the allelic preference for imbalance on chromosome 7, with at least 90% of tumors from the congenics showing preferential gain of markers on the chromosome carrying the susceptibility variant. Importantly, these alterations enabled us to refine the location of Skts1 at higher resolution than that attained using the congenic mice. We conclude that low-penetrance susceptibility genes can have strong effects on patterns of allele-specific somatic genetic changes in tumors, and that analysis of the directionality of these somatic events provides an important and rapid route to identification of germline genetic variants that confer increased cancer risk.

The effect of tissue-specific growth patterns of target stem cells on the spectrum of tumours resulting from multistage tumorigenesis.

A multistage mathematical model of tumorigenesis has been developed to explore the effects of target cell growth pattern on the proportions of tumours deriving from different tissues (the tumour spectrum). Analytical modelling techniques have shown that the effect of the target cell growth pattern on the tumour spectrum also depends on the number of stages (gene mutations) necessary for malignant change in cells of each tissue type. This suggests the existence of temporal "windows of opportunity" for tumours of different types in relation to stage number and growth kinetics. Models of this kind are applicable to cancer-prone transgenic (e.g. p53 deficient) mice, where homozygotes and heterozygotes differ in one carcinogenic stage, and differ also in the spectrum of tumours observed. Generally, tumours deriving from target stem cells which are developmentally short-lived will arise more frequently in homozygotes than heterozygotes. Such models may also be applicable to human syndromes (e.g. Li-Fraumeni) in which susceptibility to cancer is inherited.

Epistatic interactions between skin tumor modifier loci in interspecific (spretus/musculus) backcross mice.

The development of cancer is influenced both by exposure to environmental carcinogens and by the host genetic background. Epistatic interactions between genes are important in determining phenotype in plant and animal systems and are likely to be major contributors to cancer susceptibility in humans. Several tumor modifier loci have been identified from studies of mouse models of human cancer, and genetic interactions between modifier loci have been detected by genome scanning using recombinant congenic strains of mice (R. Fijneman et al., Nat. Genet., 14: 465-467, 1996; T. van Wezel et al., Nat. Genet., 14: 468-470, 1996; W. N. Frankel et al., Nat. Genet., 14, 371-373, 1996). We demonstrate here that strong genetic interactions between skin tumor modifier loci can be detected by hierarchical whole genome scanning of a complete interspecific backcross [outbred Mus spretus X Mus musculus (NIH/Ola)]. A locus on chromosome 7 (Skts1) showed a highly significant interaction with Skts5 on chromosome 12 (P < 10(-16)), whereas additional significant interactions were detected between loci on chromosomes 4 and 5, and 16 and 15. Some of these quantitative trait loci and their interactions, in particular the Skts1-Skts5 interaction, were confirmed in two completely independent backcrosses using inbred spretus strains (SEG/Pas and SPRET/Ei) and NIH/Ola. These results, therefore, illustrate the general use of interspecific crosses between Mus musculus and Mus spretus for the detection of strong genetic interactions between tumor modifier genes.

Factors affecting fetal weight distribution in women with type I diabetes.

OBJECTIVE: To identify factors independently affecting fetal weight in women with type I diabetes. DESIGN: Prospectively recorded data in consecutive women with type I diabetes, between 1975-1992. SETTING: Simpson Memorial Maternity Hospital, Edinburgh. Population Three hundred and two pregnancies with type I diabetes identified before pregnancy, with antenatal care and delivery in the Simpson Memorial Maternity Hospital, a singleton pregnancy, and the same diabetic physician. METHODS: Normal ranges for birthweight were established for the total hospital population. All cases and the total population had pregnancy dating by ultrasound. The relation between standardised birthweight and explanatory variables was investigated using correlation analysis, t tests and chi2 tests as appropriate, and subsequently using multiple linear regression. RESULTS: Standardised birthweight in cases, compared with the reference population, showed a unimodal, approximately normal distribution, markedly shifted to the right (mean + 1.26 SD). The most predictive variable was glycated haemoglobin concentration at 27-33 weeks, which explained 6.3% of the birthweight variance, while smoking explained 2.7% and maternal weight 2.0%. There was a trend towards a negative relationship with glycated haemoglobin concentration at 6-12 weeks. Smoking and glycated haemoglobin concentration were strongly intercorrelated. CONCLUSIONS: Most of the variance in standardised birthweight remains unexplained, but glycated haemoglobin concentration at 27-33 weeks is the most powerful explanatory variable. Possible reasons why there is not a stronger relationship between markers of maternal glycaemia and birthweight are discussed.