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PubMed1993

Genetic analysis of human placental aromatase deficiency.

Placental aromatase deficiency, which was characterized by maternal and fetal virilization and by a low level of estrogen excretion into urine during pregnancy, was studied by biochemical and molecular genetical techniques. Among enzymes participating in the electron transport system of the patient's placental microsomes, only aromatase activity was observed to be reduced (< 3% of normal levels). Northern and Western blotting analyses showed that the transcription of the aromatase gene and the translation of its mRNA seemed to proceed normally in the patient's tissue. However, the aromatase cDNA isolated from the patient was found to contain an extra DNA fragment of 87 base pairs (bp) which encoded 29 amino acids in frame but no termination codon. The insertion was located at the splicing point between exon 6 and intron 6 of the normal aromatase gene. The extra DNA fragment represented the first part of intron 6 except that its initial GT was altered to GC. These findings indicated that, in the patient's aromatase gene, the splicing between exon 6 and intron 6 did not occur at the normal position. This reflected the presence of one point mutation in its consensus sequence which caused the next cryptic consensus sequence 87 bp downstream, to be used according to the canonical GT/AG rule. The protein molecule thus translated contained an extra 29 amino acids. Furthermore, the patient's aromatase cDNA was observed to produce a protein molecule with a trace of activity in the transient expression system of COS-7 cells and in the high level expression system of baculovirus-insect cells. Direct DNA sequencing of aromatase genes from the patient and parents confirmed that this deficiency is a hereditary disease with an autosomal recessive inheritance pattern. The patient and parents are homozygote and heterozygotes, respectively, for this mutation.

Amino Acid Sequence↗
PubMed1993

Genetic analysis by DNA fingerprinting in tsetse fly genomes.

Genomic DNA from tsetse flies (Diptera: Glossinidae: Glossina Wiedemann) was analyzed by hybridization using the whole M13 phage as a probe to reveal DNA fingerprinting (DNAfp) profiles. Intrapopulation variability, measured by comparison of DNAfp profiles of tsetse flies from a large colony of G. brevipalpis, showed a high degree of polymorphism similar to that found in other animal species. Different lines of G. m. morsitans, G. m. centralis, G. m. submorsitans, G. p. palpalis and G. p. gambiensis established from small colonies displayed less genetic variability than the G. brevipalpis population. The analysis of pedigree relationships within an inbred line of G. m. centralis conformed to a Mendelian inheritance pattern. In the pedigree presented no mutations were observed, one fragment was linked to the X chromosome, and three fragment sets were linked, but most fragments showed independent segregation. M13 revealed no characteristic DNAfp profile differences between the subgenus Glossina and the subgenus Nemorhina, but a conserved distribution pattern was found in the laboratory colonies within each subspecies. M13 also revealed line specific DNA fragments that may be useful as genetic markers to expand the present linkage map of G. m. morsitans.

Animals↗
PubMedDate not supplied

Cerebro-costo-mandibular syndrome presenting as Pierre Robin sequence.

Cerebro-costo-mandibular syndrome is a rare disorder characterized by psychomotor retardation, posterior rib-gap defects, and the orofacial defects of Pierre Robin sequence. Most cases are sporadic, but several familial cases have been reported, many of which support autosomal recessive inheritance. We present a case of autosomal dominant inheritance from father to son; the seventh known case of dominant transmission. We also review the findings, inheritance pattern, and outcomes of Pierre Robin sequence that are useful in managing affected patients.

Abnormalities, Multiple↗
PubMedDate not supplied

Genes and type 2 diabetes mellitus.

Type 2 diabetes (T2DM) comprises a group of entities with different genetic causes. In most patients, T2DM results from alterations of various genes, each having a partial and additive effect. The inheritance pattern is thus complex, and environmental factors play an important role in favoring or delaying the expression of the disease. The identification of susceptibility genes and genetic variants requires different methodological approaches. Here we address some of the most important strategies and findings on the genomic basis of T2DM, as well as evidence of genetic heterogeneity among populations. The identification of the underlying genetic causes of T2DM and other related traits such as obesity and hypertension will lead to the development of new therapeutic targets likely to impact the way we treat these diseases. Survival and quality of life for T2DM patients is expected to eventually increase, significantly lessening the socioeconomic burden of the disease.

Alleles↗
PubMed2003

Hepatocyte nuclear factor 1 negatively regulates amylin gene expression.

Maturity-onset diabetes of the young (MODY) is a monogenic subtype of Type 2 diabetes, defined as having an early age of onset, with a dominant inheritance pattern. Hepatocyte nuclear factor 1 (HNF1), which is encoded by the MODY3 gene, has been shown to bind the insulin promoter. Since the promoters of three pancreas-specific genes involved in glucose homeostasis-insulin, glucokinase, and amylin bind similar transcription factors, we were interested in whether HNF1 could also regulate amylin expression. In the present study, we used the electrophoretic mobility shift assay, to demonstrate that the HNF1 transcription factor can specifically bind to the amylin promoter. Moreover, co-transfection of an HNF1 expression vector with an amylin-CAT reporter plasmid decreased the activity of the amylin promoter by 85%. These data support the hypothesis that the amylin gene is regulated by HNF1 in a negative manner and may explain partially how HNF1 mutations result in diabetes.

Amyloid↗
PubMed2006

Maternally inherited non-syndromic hearing loss associated with mitochondrial 12S rRNA A827G mutation in a Chinese family.

We explored the clinical and molecular characterization of a Chinese family with non-syndromic hearing impairment. Clinical evaluations revealed a possible maternal inheritance pattern, and showed an extremely similar phenotype of hearing loss including the age of onset, severity, and audiometric configuration. Sequence analysis of the mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes led to the identification of a homoplasmic A827G mutation in all maternal relatives, which was absent in other family members and 40 Chinese controls. This mutation has previously been reported sporadically in a few individuals with aminoglycoside-induced and non-syndromic hearing loss. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly evolutionarily conserved in mammals. The occurrence of the A827G mutation in these genetically unrelated subjects strongly suggests that this mutation is involved in the pathogenesis of hearing impairment. However, incomplete penetrance of hearing loss indicates that the A827G mutation alone is not sufficient to produce clinical phenotype but requires the involvement of modifier factors for the phenotypic expression, even though aminoglycosides and GJB2 gene may not contribute to the penetrance of the A827G mutation in this Chinese family. In contrast with the variable phenotype of hearing loss associated with other mitochondrial mutations, all of the patients in our family exhibited strikingly similar clinical features. This discrepancy likely reflects the difference of genetic backgrounds between this pedigree and others.

Asian People↗
PubMed2006

Functional characterization of CLCN1 mutations in Taiwanese patients with myotonia congenita via heterologous expression.

Mutations in the CLCN1 gene frequently associate with myotonia congenita (MC). We have recently reported several CLCN1 mutants in Taiwanese patients. To further elucidate the correlation between the genotypes and phenotypes, in this study, we used Xenopus oocyte as a system to investigate the functional effects of these mutants. The fs793X and G482R mutants, which were suggested to have a dual inheritance pattern, were found to cause a functional loss of CLCN1 channels. While co-expression of fs793X and wild-type (WT) showed a reduction of chloride conductance by about half of WT channels, the activation curve of voltage-dependence was not shifted. A compound heterozygous mutant, P575S/D644G, was found in a patient. When both mutants were co-expressed in oocytes, they caused a shift of the voltage-dependence of activation curve to more positive values than individual mutant. This indicates that both P575S and D644G mutants may contribute cooperatively to change the gating property of CLCN1 channel. Interestingly, the S471F mutant did not cause significant alternation of functional properties. Consistent with the fact that T631I mutant was found in three asymptomatic individuals, the electrophysiological parameters of T631I were similar to those of WT CLCN1 channels, suggesting that T631I is a neutral mutation. These results further clarify the correlation between the mutations and their functional implications of CLCN1 channels.

Animals↗
PubMed2006

Skin wound healing in the first generation (F1) offspring of Yorkshire and red Duroc pigs: evidence for genetic inheritance of wound phenotype.

Fibroproliferative scars in humans often demonstrate familial inheritance patterns, and genetics may contribute to healing and scarring. Genetic factors may also influence the scarring phenotype in a porcine model. Healing of full thickness excisional skin wounds in Yorkshire pigs closely resembles normal healing in humans, while identical wounds in red Duroc pigs form hypercontracted, hyperpigmented scars. The present study has evaluated the healing process in the first generation cross (F1) of red Duroc and Yorkshire pigs. Gross and histologic analysis revealed that the F1 animals exhibit an intermediate healing phenotype, with some features of each parent breed. F1 full thickness wounds were significantly hypercontracted and fibrotic, but apigmented. Analysis of mRNA expression patterns for a panel of relevant molecules (N=32) in the F1 animals revealed some similarities to each parent breed, as well as unique patterns for other molecules. Furthermore, a depth dependency to the healing response was observed at the gross, histologic, and molecular levels, with deep dermal wounds healing similar to Yorkshire wounds. These findings suggest that the genetic contribution to scar phenotype in this animal model is complex. However, the results indicate that further understanding in this model may provide insights into risk factors for hypertrophic scarring in human burn patients.

Animals↗
PubMed2004

GST profiling may be useful in the screening for thyroid nodule malignancy.

Screening tools are of utmost necessity in order to identify individuals at risk for thyroid nodule cancer. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the Glutathione-S-Transferase (GST) system, plays an important role in the development of most human cancers. GSTP1 enzyme is the most important detoxification enzyme in human head and neck tissues. An aminoacid substitution (1105V) in the GSTP1 gene result in two genotypes, GSTP1AB and GSTP1BB. Those produce a variant enzyme with lower activity and less capability of effective detoxification of carcinogens than the wild type GSTP1AA. In order to look for the influence of GSTP1 enzymes inheritance pattern on thyroid cancer risk we used a PCR-SSCP-sequencing approach to compare the genotypes of 98 malignant nodules, including 77 papillary carcinomas (PC) and 21 follicular carcinomas (FC), to 44 benign nodules and to 157 healthy control individuals. Individuals with history of previous thyroid disease, exposure to radiation and antecedents of malignancy were excluded. Patients with PC and FC showed a significant over-representation of the variants of GSTP1 allele compared to the control population (p < 0.0001 The risk for thyroid cancer in individuals with the variant GSTP1 enzymes, after adjusting for gender, age, tobacco and drugs use, increased 7,092 (CI: 2,307-21,802) and 9,625 (CI: 2.484-37.291) times for PC and FC, respectively. We suggest that GST genotype may be associated with an increased susceptibility to thyroid cancer. GSTP1 profiling from peripheral blood may be a simple and useful tool in the screening for thyroid nodule malignancy. Glutathione-S-Transferase system; GSTP; Thyroid cancer; Screening.

Adenocarcinoma, Follicular↗
PubMed2006

The variable expression of keratoconus within monozygotic twins: dundee University Scottish Keratoconus Study (DUSKS).

INTRODUCTION: As part of a longitudinal observational prospective study (Dundee University Scottish Keratoconus Study, DUSKS) a caucasian female subject was identified with keratoconus affecting both corneas. Of interest was that the subject's mother was a monozygotic twin, however, the mother was reportedly unaffected by keratoconus, although her sister (the subject's aunt) had been diagnosed with keratoconus. METHOD: Computer video-keratoscopy (CVK) was undertaken was on this family to clarify this apparent discordance. RESULTS: CVK demonstrated the variable expression of the keratoconic phenotype, by identifying evidence of subclinical keratoconus in the 'unaffected' twin. CONCLUSION: So far only one set of monozygotic twins with keratoconus have been reported within the UK, this paper reports a second. Since CVK has been available the majority agree on concordance of keratoconus expression but not all, including this study. If monozygotic twin studies demonstrate heterogeneity of keratoconus this may at least explain the contradictory data that exists within the literature and why the inheritance pattern of keratoconus is still unclear in 2005.

Corneal Topography↗
PubMed2004

A fourfold difference in the incidence of type 1 diabetes between Sweden and Lithuania but similar prevalence of autoimmunity.

We investigated whether other autoimmune disorders in addition to type 1 diabetes are more common in Sweden than Lithuania, and if there are any differences in inheritance patterns of both type 1 diabetes and other autoimmune disorders. Data from 517 children in southeast Sweden and 286 children in Lithuania aged 0-15 years were included in the study. Age- and sex-matched control children were randomly selected. Information was collected by questionnaire. Of the children with diabetes in Sweden, 13.2% had a family member with type 1 diabetes compared to 7% of children with diabetes in Lithuania (P < 0.01) (OR = 2.01). No such difference was seen for other autoimmune diseases in family members of children with diabetes (Sweden 12%, Lithuania 14%, n.s.). Control children in Lithuania had family members with autoimmunity more frequently (15.3%) than control children in Sweden (7.4%, P < 0.001) (OR = 2.26). This difference was most pronounced in mothers. The Lithuanian control children had an autoimmune disease more frequently than the controls in Sweden (4.7% versus 1.5%, respectively, P < 0.001) (OR = 3.21). There seem to be environmental factors that specifically contribute to the development of type 1 diabetes, factors which are less related to the development of autoimmunity in general.

Adolescent↗
PubMed2006

Germline mutations and gene polymorphism associated with human pancreatitis.

A wide range of mutations and polymorphisms in genes that relate to pancreatic function seem to be involved in the development of pancreatitis. Some of these genetic alterations lead to disease phenotypes with unequivocal mendelian inheritance patterns, whereas others seem to act as modifier genes in conjunction with environ-mental or, as yet unidentified, genetic cofactors. This article reviews germline changes in the genes for trypsin, pancreatic secretory trypsin inhibitor, the cystic fibrosis conductance regulator, lipid metabolism proteins, inflammatory mediators for cytokines, and cathepsin B.

Carrier Proteins↗
PubMed2006

Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism.

OBJECTIVE: To characterize the phenotype, modes of inheritance, karyotype, and molecular basis of patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Review of medical records, karyotyping, and collation of gene mutation analysis. SETTING: University molecular reproductive endocrinology laboratory. PATIENT(S): Patients with IHH. INTERVENTION(S): Review of medical records, laboratory studies, and molecular studies. MAIN OUTCOME MEASURE(S): Sense of smell, severity of IHH (complete vs. incomplete), associated anomalies, karyotype, mutation analysis, and genotype/phenotype correlations were studied. RESULT(S): Of 315 patients with IHH, 6.3% had one or more affected relatives. Autosomal recessive inheritance was likely in most of these familial cases, but autosomal-dominant and X-linked recessive inheritance patterns were likely in some families. Complete IHH was more commonly found in males (62%), whereas incomplete IHH was more commonly observed in females (54.3%). Anosmia was present in 31.3% of males and 27.9% of females. The karyotype was normal in all 19 females tested, but was abnormal in 3 of 57 (5.3%) of males tested. Although cryptorchidism did not differ among those who were anosmic vs. normosmic, it was approximately four times more common in patients with complete IHH than incomplete IHH (15.3% vs. 3.9%). Approximately 10% of the IHH patients tested had mutations in either the GNRHR or KAL1 gene. CONCLUSION(S): Idiopathic hypogonadotropic hypogonadism is a heterogeneous disorder affecting fertility, in which the number of familial cases is probably underestimated. Further study of genes that regulate hypothalamic-pituitary development and function will likely reveal important information regarding the development of normal puberty in humans.

Adolescent↗
PubMed2004

Primer binding site mutations affecting the typing of STR loci contained within the AMPFlSTR SGM Plus kit.

The Forensic Science Service carries out human identification and familial investigations using the AMPFlSTR SGM Plus kit (PE Biosystems, Warrington, England). We have studied approximately 42,000 parent/child allelic transfers (meioses) for deviations from expected Mendelian Inheritance patterns. Of 55 apparent mutations detected, 20 had patterns suggestive of the presence of a primer binding site mutation producing a silent/null allele. The presence of a silent allele was unequivocally demonstrated in 13 of the 20 suspected cases by using alternative primer sets. Of the 13 confirmed cases, 9 involved the D18S51 locus. As the individuals in these cases all originated from the same geographic region of the Middle East, this cluster suggests the presence of a relatively common variant D18S51 allele in that particular group. These data taken together with our previously published work, confirm that the primer binding sites utilised for amplification of the loci contained in the AMPFlSTR SGM Plus kit have highly conserved nucleotide sequences.

Alleles↗
PubMed2004

Medical management of the pregnant patient with inflammatory bowel disease.

Gastroenterologists are not infrequently faced with questions regarding pregnancy when advising or treating their patients with inflammatory bowel disease (IBD). To advise patients effectively, the following factors must be considered: (1) the inheritance patterns of IBD for accurate counseling and family planning; (2) the effects of active IBD versus medications or surgery on fertility; (3) the effects of pregnancy on the course of IBD; (4) the effects and potential risks of active IBD versus those of diagnostic tests, medical treatments, and surgical treatments on the developing fetus; (5) approach to delivery; and (6) the risks of breast-feeding while receiving treatment for IBD.

Adrenal Cortex Hormones↗
PubMed2006

Endogenous T lymphocytes and microglial reactivity in the axotomized facial motor nucleus of mice: effect of genetic background and the RAG2 gene.

Following facial nerve axotomy in mice, peripheral T cells home to the injured facial motor nucleus (FMN) where they may influence the glial response. Interactions between T cells and microglia, which proliferate in response to axotomy, appear to confer neuroprotection to injured motoneurons. The primary objective of this study was to determine whether T lymphocytes could influence the microglial reaction to motoneuron injury. These experiments tested the hypotheses that (1) C57BL/6 (B6) and 129 mice, inbred strains which have high and low levels of astroglial reactivity in the axotomized FMN, respectively, would also exhibit high and low levels of T cell infiltration, and (2) that these differences would correspond with levels of microglial reactivity and neuronal regeneration. Thus, we compared the response to facial nerve axotomy in B6, 129, and immunodeficient RAG2 knockout (RAG2 KO) mice on these two backgrounds at 14 day post-axotomy for differences in levels of 1) CD3+ T cell infiltration; (2) major histocompatibility complex II (MHC2) expression by microglia; (3) perineuronal microglial phagocytic clusters, an indirect measure of neuronal death; and (4) overall microglial activity as assessed by CD11b expression. To examine the inheritance pattern of the abovementioned neuroimmune measures, we also made assessments in B6x129 F1 generation mice. B6 and 129 mice displayed high and low levels of T cell infiltration to the affected FMN and low and high MHC2 expression, respectively. Levels of microglial activity did not differ between the two strains. In immunodeficient RAG2 KO mice on both backgrounds, the number of MHC2+ microglia did not differ from their immunologically normal background controls. Moreover, deletion of either the RAG2 or RAG1 genes in B6 mice was not associated with increased neuronal death at day 14 post-axotomy, as we had previously found in B6 mice with the severe combined immunodeficiency (SCID) mutation. Contrary to our hypothesis, the paucity of T cells in the affected FMN of the 129 mice was associated with less neuronal death when compared to B6 mice, which showed a robust T cell response. Moreover, the data suggest that parameters of the central and peripheral immune responses to axotomy are independently regulated. Assessments in B6x129 F1 generation mice revealed dominant phenotypes for both T cell infiltration and neurodegeneration, whereas both strains contributed significantly to the phenotype for MHC2 expression. Our findings suggest that (1) T cells do not appear to modify measures of microglial reactivity in the axotomized FMN; and (2) the impact of T cells on injured motoneurons in immunologically intact mice and in immunodeficient mice grafted with T cells by adoptive transfer may be different. Further study is required to understand the role of T cells following motoneuron injury in immunologically intact mice and how the seemingly divergent effects of T cells in intact and immunodeficient mice might provide insight into their role in neuronal injury and repair.

Analysis of Variance↗
PubMed2006

Investigation of the G protein subunit Galphaolf gene (GNAL) in attention deficit/hyperactivity disorder.

The dopamine system plays an important role in the regulation of attention and motor behavior, subsequently, several dopamine-related genes have been associated with Attention Deficit/Hyperactivity Disorder (ADHD). Among them are the dopamine receptors D1 and D5 that mediate adenylyl cyclase activation through coupling with G(s)-like proteins. We thus hypothesized that the G(s)-like subunit Galpha(olf), expressed in D1-rich areas of the brain, contributes to the genetic susceptibility of ADHD. To evaluate the involvement of the Galpha(olf) gene, GNAL, in ADHD, we examined the inheritance pattern of 12 GNAL polymorphisms in 258 nuclear families ascertained through a proband with ADHD (311 affected children) using the transmission/disequilibrium test (TDT). Categorical analysis of individual marker alleles demonstrated biased transmission of one polymorphism in GNAL intron 3 (rs2161961; P=0.011). We also observed significant relationships between rs2161961 and dimensional symptoms of inattention and hyperactivity/impulsivity (P=0.003 and P=0.008). In addition, because of recent evidence of imprinting at the GNAL locus, secondary analyses were split into maternal and paternal transmissions to assess a contribution of parental effects. We found evidence of strong maternal effect, with preferential transmission of maternal alleles for rs2161961A (P=0.005) and rs8098539A (P=0.035). These preliminary findings suggest a possible contribution of GNAL in the susceptibility to ADHD, with possible involvement of parent-of-origin effects.

Adolescent↗
PubMed2005

A genetic and genomic approach to identify longevity genes in mice.

Natural variation in rate of aging or longevity in mice and humans shows a very complex inheritance pattern. Few targeted genetic screens have identified longevity genes in mammals, partly as a result from the fact that the genetics of longevity can only be studied reliably in cohorts of mice. In this paper we propose that a combined genetic and genomic analysis of large families of fully genotyped recombinant inbred mice may provide a crucial tool to the aging research community. As a proof of principle we describe preliminary studies in which variation in gene expression patterns in hematopoietic stem cells and brain were genetically linked to longevity.

Animals↗