ABSTRACT
Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.
Subject(s)
Dementia/genetics , Mutation , Parkinsonian Disorders/genetics , tau Proteins/genetics , Adult , Amino Acid Substitution , Behavior , Brain/pathology , Cognition Disorders/etiology , Cysteine , Dementia/metabolism , Dementia/pathology , Dementia/psychology , Humans , Male , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/psychology , Pedigree , Personality , Phenotype , Protein Isoforms/metabolism , Threonine , tau Proteins/metabolismABSTRACT
BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation. METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively. RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen. CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.
Subject(s)
Brain Diseases/etiology , Calcinosis/etiology , Cerebrovascular Disorders/complications , Cysts/etiology , Retinal Diseases/complications , Retinal Vessels , Adolescent , Bone Diseases/diagnostic imaging , Bone Diseases/etiology , Brain Diseases/diagnosis , Calcinosis/diagnosis , Calcinosis/pathology , Cerebrovascular Disorders/pathology , Child, Preschool , Female , Hemangioma/complications , Humans , Leukoencephalopathy, Progressive Multifocal/diagnosis , Leukoencephalopathy, Progressive Multifocal/etiology , Magnetic Resonance Imaging , Male , Microcirculation , Retinal Diseases/diagnosis , Retinal Neoplasms/complications , Syndrome , Telangiectasis/complications , Tomography, X-Ray ComputedABSTRACT
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15-29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.
Subject(s)
Fumarate Hydratase/genetics , Genetic Predisposition to Disease , Germ-Line Mutation , Neoplasms/genetics , Adolescent , Adult , Age Factors , Aged , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/genetics , Cohort Studies , Female , Finland , Humans , Kidney Neoplasms/diagnosis , Kidney Neoplasms/genetics , Leiomyomatosis/diagnosis , Leiomyomatosis/genetics , Male , Middle Aged , Neoplasms/diagnosis , Phenotype , Risk FactorsABSTRACT
The placenta is responsible for the production of progesterone (P) and estrogens during human pregnancy. In this study, the expression of several key steroidogenic enzymes was investigated in different cell types of human placenta during early and mid-gestation by in situ hybridization. 3Beta-hydroxysteroid dehydrogenase type 1 (3beta-HSD1), P450 aromatase (P450arom) and 17beta-hydroxysteroid dehydrogenase type 1 (17HSD1) were expressed abundantly in syncytiotrophoblast (ST) cells. These three enzymes were also detected in some column cytotrophoblast (CCT) cells. 17HSD5 was found in intravillous stromal (IS) cells in low levels, suggesting that androgens may be synthesized and metabolized in the placenta. 17HSD7 was found in all types of placental cells. Moreover, 17HSD2 was localized in IS cells. The expression level of 17HSD2 gradually increased during pregnancy weeks 7-16, concurrently with the androgen production by the male fetus. The present study provides evidence that CCT and IS cells participate in P and estrogen biosynthesis, in addition to ST cells. 17HSD2 also converts 20alpha-dihydroprogesterone (20-OH-P) to P, whereas 17HSD5 and 17HSD7 inactivate P. Therefore, the action of 3beta-HSD1 and 17HSD2 on P biosynthesis in the placenta is countered by 17HSD5 and 17HSD7, which may provide an optimal level of P for the maintenance and progression of pregnancy.
Subject(s)
17-Hydroxysteroid Dehydrogenases/genetics , 3-Hydroxysteroid Dehydrogenases/genetics , Aromatase/genetics , Placenta/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , 17-Hydroxysteroid Dehydrogenases/metabolism , Androgens/biosynthesis , Estrogens/biosynthesis , Female , Fetus/metabolism , Gene Expression , Humans , Immunohistochemistry , In Situ Hybridization , Male , Placenta/cytology , Placentation , Pregnancy , Progesterone/biosynthesisABSTRACT
Matrix metalloproteinases (MMPs) are responsible for extracellular matrix (ECM) degradation, and their functions are regulated by tissue inhibitors of MMPs (TIMPs). The evidence for the roles of MMPs and TIMPs in implantation and placentation has remained insufficient in humans, especially during the early stages. Tubal pregnancy has some similarities to normal intrauterine pregnancy and therefore may provide a unique model for implantation studies. In the present study, the expression of MMP-2, -9 and -14, and TIMP-1, -2 and -3 at the feto-maternal interface during tubal pregnancy was examined by immunohistochemistry and in situ hybridization. We found that MMP-9 and TIMP-1, -2 and -3 are produced by all types of extravillous cytotrophoblast (EVCT) cells, while MMP-2 and -14 mainly exist in distal column cytotrophoblast (CCT) cells and invasive EVCT cells. Meanwhile, the intensity of MMP-14 and TIMP-1 and -2 increased along the invasive pathway toward maternal interstitium. In addition, MMP-2, -9 and -14 and TIMP-1, -2 and -3 were all detected in the villous CT (VCT) cells. Furthermore, both the mRNA level and immunoreactivity of MMP-9, TIMP-1 and -3 increased, while those of TIMP-2 decreased concurrent with the progression of pregnancy during weeks 3-9. The unique expression pattern of various MMPs and TIMPs at the feto-maternal interface suggests that they may have roles in regulating the controlled invasion of trophoblasts during implantation and placentation. Meanwhile, the study provides a better understanding of the mechanisms involved in cellular events during human pregnancy, especially at the initiation stage of implantation.
Subject(s)
Embryo Implantation , Fallopian Tubes/enzymology , Matrix Metalloproteinases/analysis , Pregnancy, Tubal/enzymology , Tissue Inhibitor of Metalloproteinases/analysis , Female , Humans , Matrix Metalloproteinase 2/analysis , Matrix Metalloproteinase 9/analysis , Matrix Metalloproteinases, Membrane-Associated , Metalloendopeptidases/analysis , Pregnancy , Pregnancy Trimester, First , Tissue Inhibitor of Metalloproteinase-1/analysis , Tissue Inhibitor of Metalloproteinase-2/analysis , Tissue Inhibitor of Metalloproteinase-3/analysisABSTRACT
BACKGROUND: Deposition of the beta-amyloid peptide (Abeta) in neuritic plaques is a hallmark of Alzheimer disease (AD). Mutations in genes encoding amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) are associated with increased accumulation of Abeta in neuritic plaques or in the walls of cerebral vessels. Intracerebral hemorrhage occasionally affects patients with AD. METHODS: A Finnish family with dementia in four generations and with frequent co-occurrence of dementia and intracerebral hemorrhage was identified. Clinical features of 14 family members with a cognitive decline were evaluated. All exons in genes encoding APP, PSEN1, PSEN2, cystatin C, transthyretin, gelsolin, and ITM2B were sequenced, and an association study of APP was conducted by identification of single-nucleotide polymorphisms. RESULTS: Neuropathologic examination revealed Alzheimer-type changes with Abeta in neuritic plaques and vessel walls, but the cognitive profile of the patients differed from that in AD, as the visuoconstructive functions and verbal fluency were well preserved even in the moderate stage of the disease. In addition to cognitive decline, five patients had had lobar intracerebral hemorrhages and one was diagnosed with hemosiderin deposits in MRI, suggesting previous cerebral microbleeds. No causative mutations were identified in candidate genes associated with amyloid diseases, but linkage to APP region could not be entirely excluded. CONCLUSIONS: The family presents an autosomal dominant form of beta-amyloidogenic disease that resembles the Italian, Flemish, and Iowa types of AD. No amyloidogenic mutations were identified, but the role of the APP region could not be entirely excluded.
Subject(s)
Cerebral Amyloid Angiopathy/epidemiology , Cerebral Hemorrhage/epidemiology , Dementia/epidemiology , Adult , Age of Onset , Alzheimer Disease/classification , Alzheimer Disease/diagnosis , Alzheimer Disease/psychology , Biopsy , Brain/diagnostic imaging , Brain/pathology , Brain Chemistry , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/genetics , Cerebral Amyloid Angiopathy/pathology , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/genetics , Cerebral Hemorrhage/pathology , DNA Mutational Analysis , Dementia/diagnosis , Dementia/diagnostic imaging , Dementia/genetics , Dementia/pathology , Dementia/psychology , Diagnosis, Differential , Female , Finland , Genes, Dominant , Genetic Heterogeneity , Haplotypes/genetics , Hemosiderin/analysis , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Pedigree , Plaque, Amyloid , Polymorphism, Restriction Fragment Length , Polymorphism, Single Nucleotide , Positron-Emission Tomography , Tomography, X-Ray ComputedABSTRACT
Investigation of the expression pattern of integrins and their extracellular matrix (ECM) ligands in trophoblasts at the maternal-fetal interface during tubal pregnancy may aid better understanding of the adhesion and invasion of acceptable maternal endometrium by trophoblast cells at the very early stage of human gestation. In this study, spatial and temporal alterations of integrins and ECM ligands were examined in specimens of tubal pregnancies during weeks 3-9 of gestation. In situ hybridization and immunohistochemistry revealed that relatively high levels of integrin alpha(1), beta(1), alpha(5) subunits and heterdimer alpha(5)beta(1) as well as ECM ligands, were displayed in trophoblast cells as early as weeks 3-4 of gestation. Expression peaked during weeks 5-7 and then, with the exception of integrin alpha(1), which remained high, declined slightly up to weeks 8-9 of gestation. Immunoreactive fibronectin, laminin and type IV collagen were detected in column cytotrophoblastic cells (CTB) and some invasive extravillous cytotrophoblast (EVCT) cells and the alterations were coincident with those of the corresponding integrin receptors in EVCT cells. Laminin was strongly stained in EVCT cells that had invaded maternal blood vessels and deep into the interstitium. Maternal epithelial, endothelial and stromal cells also expressed these integrins and ECM ligands. The results indicate their involvement in mediating the adhesion of trophoblasts to the epithelium of the maternal Fallopian tube. The upregulated expression of these molecules in column CTB and invasive EVCT cells may also facilitate the invasion of trophoblasts into the maternal interstitium. Moreover, trophoblasts possessed the potential for self-controlled adhesion and invasion and appear to reach peak invasive capability in the second month of tubal implantation.
Subject(s)
Extracellular Matrix Proteins/analysis , Fallopian Tubes/chemistry , Integrins/analysis , Pregnancy, Tubal/metabolism , Trophoblasts/chemistry , Collagen Type IV/analysis , Embryo Implantation , Endothelial Cells/chemistry , Epithelial Cells/chemistry , Female , Fibronectins/analysis , Gestational Age , Humans , Immunohistochemistry/methods , In Situ Hybridization/methods , Integrin alpha1/analysis , Integrin alpha5/analysis , Integrin beta1/analysis , Laminin/analysis , PregnancyABSTRACT
We present a case report of acute bilateral excercise-induced compartment syndrome in the adductor longus muscles, which was treated with bilateral medial fasciotomies. Postoperatively, the healing process of the adductor muscles was followed up by repeated MR imagings over six months. Myonecrosis was found in peroperative muscle biopsies. Pain and muscle swelling subsided soon after the fasciotomy, correlating with the early postoperative MR findings. Four months postoperatively, the signal intensity of the adductor muscles was normal in T1- and T2-weighted images, but the normal fibre structure of the adductor muscles could only be seen 6 months postoperatively. At six month's control checkup there was no subjective weakness of the adductors, and hyperesthesia had disappeared and the patient was capable of normal activities.
Subject(s)
Athletic Injuries/diagnosis , Compartment Syndromes/diagnosis , Magnetic Resonance Imaging/methods , Thigh/injuries , Adult , Athletic Injuries/surgery , Compartment Syndromes/etiology , Compartment Syndromes/surgery , Follow-Up Studies , Humans , Male , Muscle, Skeletal/injuries , Treatment OutcomeABSTRACT
We describe MR findings of a nasal glioma in a 5-week-old male infant with feeding difficulties and symptoms of respiratory distress. Endoscopic examination revealed a soft tissue mass in the nasal cavity. In T1- and T2-weighted images, the gyral structure of grey matter was visible. In T1-weighted images, a tissue component with a lower signal intensity equal to that of white matter was also well distinguishable. Edge enhancement of the tumour was due to the nasal mucosal epithelium covering the tumour. MR images were useful to rule out intracranial extension of the nasal cavity lesion and the brain, thus excluding the diagnosis of encephalocele. The lesion was excised and histologically characterized as heterotopic brain tissue.
Subject(s)
Brain , Choristoma/diagnosis , Magnetic Resonance Imaging , Nose Diseases/diagnosis , Humans , Infant , MaleABSTRACT
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by cerebral symptoms, but peripheral nerve or muscle involvement has not been reported. We describe a patient who had a stereotypic clinical presentation of CADASIL and, in addition, myopathy with ragged-red fibers, suggesting a mitochondrial disorder. Therefore we determined the nucleotide sequence in the entire coding region of the patient's mtDNA by conformation-sensitive gel electrophoresis and sequencing. Sequence of the exon 4 in the Notch3 gene was determined in a similar fashion. We found that the patient had myopathy with ragged-red fibers, and ultrastructural examination revealed mitochondrial aberrations. CADASIL was due to an R133C mutation in Notch3; in addition, we found a novel mutation 5650G>A in the tRNAAla gene in mtDNA. The mutation was heteroplasmic, with the proportions of the mutant genome being 99% in muscle, 96% in the buccal epithelium, 95% in the skin, and 65% in the blood. The absence of the mutation in a maternal cousin four times removed indicated that it was new in the pedigree. We suggest that the mtDNA mutation is pathogenic, as it was associated with a relevant clinical phenotype, it was not found among controls, and it altered a structurally important segment in the amino acid acceptor stem in the tRNAAla. Furthermore, its absence in nine patients from five families with R133C suggests that its relationship with the Notch3 mutation is coincidental.
Subject(s)
DNA, Mitochondrial , Dementia, Multi-Infarct/genetics , Muscular Diseases/genetics , Mutation , Proto-Oncogene Proteins/genetics , Receptors, Cell Surface , Base Sequence , Brain/pathology , Cloning, Molecular , Exons , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Molecular Sequence Data , Muscles/ultrastructure , Nucleic Acid Conformation , Phenotype , Polymerase Chain Reaction , RNA, Transfer, Ala/genetics , Receptor, Notch3 , Receptors, NotchABSTRACT
Fetal development and tumor progression both require a complex system of extracellular matrix (ECM) synthesis and breakdown, which is mediated by, for instance, the matrix metalloproteinases (MMPs). Human metalloelastase (MMP-12) is an MMP, the expression of which has so far been documented in macrophages associated with atherosclerosis, wound repair, and certain cancers. In this study we first examined the expression of MMP-12 during human fetal development. By in situ hybridization MMP-12 transcripts were detected in chondrocytes of hypertrophic cartilage in vertebrae of the spinal column, in ribs, and in extremities undergoing ossification, beginning at the gestational age of 8 weeks. Also, periosteal cells expressed MMP-12 at 11 weeks. No expression of MMP-12 mRNA could be noted in other fetal tissues, including the skin, lungs, intestine, kidney, and liver. Expression of MMP-12 mRNA could not be detected in adult normal cartilage or osteosarcomas, but in chondrosarcomas both macrophages (8 of 19 samples) (identified by CD68 immunostaining) and chondrosarcoma cells (8 of 19) were positive. MMP-12 was also demonstrated in the tumors by western blotting and it was expressed in the same regions as MMP-13 mRNA. By immunostaining, MMP-12 mRNA colocalized with the protein in both fetal and chondrosarcoma specimens. Unlike basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) induced MMP-12 mRNA production in chondrosarcoma-derived HTB-94 cells. Our results suggest that MMP-12 plays an important role in ECM remodeling during fetal bone development and is induced when chondrocytes undergo malignant transformation.
Subject(s)
Bone Neoplasms/physiopathology , Cartilage/embryology , Chondrocytes/physiology , Chondrosarcoma/physiopathology , Metalloendopeptidases/genetics , Cartilage/cytology , Cell Transformation, Neoplastic , Cells, Cultured , Chondrocytes/cytology , Chondrocytes/drug effects , Collagenases/genetics , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/physiology , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/physiology , Humans , Macrophages/enzymology , Matrix Metalloproteinase 12 , Matrix Metalloproteinase 13 , RNA, Messenger/analysis , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Tenascin-C is an extracellular matrix glycoprotein that is spatially expressed during organogenesis, in inflammatory and fibrotic disorders, and in neoplasms. The aim of this study was to analyze its expression in developing human lung tissues during pseudoglandular, canalicular, saccular, and alveolar periods corresponding to Weeks 12 to 40. Lung tissues were obtained at autopsy from 34 nonmalformed cases. An immunohistochemical analysis and a messenger RNA (mRNA) in situ hybridization method combined with light microscopy were used. The extent of tenascin-C immunoreactivity was scored as absent, low, moderate, or strong in and around different types of pulmonary cells. The immunohistochemical expression for tenascin-C was strong beneath the airway epithelium, especially at the sites of airway subdivision during Weeks 12 to 23, whereas its expression was moderate or weak underneath alveolar and bronchiolar epithelia between Weeks 24 and 40. The expression for tenascin-C was strong in the intima of veins, especially in the canalicular period, i.e., Weeks 17 to 28. A moderate or strong immunoreactivity for tenascin-C was also observed around chondrocytes in every case studied during all periods. The increased expression of tenascin-C mRNA was most often seen in the cells below the airway epithelium. Taken together, tenascin-C is expressed in human lung during all developmental periods, and its expression is especially strong below the airway epithelium at the sites of airway subdivision.
Subject(s)
Lung/chemistry , Tenascin/analysis , Gestational Age , Humans , Immunohistochemistry , In Situ Hybridization , Infant, Newborn , Lung/embryology , Lung/growth & development , RNA, Messenger/analysis , RNA, Messenger/genetics , Tenascin/geneticsABSTRACT
Epilepsy is a common manifestation in all childhood-onset forms of neuronal ceroid lipofuscinosis. In order to document hippocampal lesions and their relationship to epilepsy we studied autopsy specimens from the hippocampi of a series of patients with the infantile (CLN1), classic late infantile (CLN2), Finnish variant late infantile (CLN5), and juvenile (CLN3) neuronal ceroid-lipofuscinosis as well as Northern epilepsy (CLN8), using a battery of histological and immunocytochemical staining methods. Despite striking differences in the overall degree of neocortical neuronal storage and loss, these genetically heterogeneous forms of neuronal ceroid lipofuscinosis showed a common lesional pattern in the hippocampi: a relative sparing of the CA1 sector and severe involvement of the neighbouring CA2 sector, with intermediate degrees of involvement of the CA3 and CA4 sectors. These findings distinguish the hippocampal pathology associated with the neuronal ceroid lipofuscinoses from classical 'mesial temporal sclerosis' and show that the selective lesional pattern in the neuronal ceroid lipofuscinoses is not a secondary anoxic-ischaemic phenomenon. It is rather a consequence of the primary metabolic defects and may be directly involved in the causation of the epileptic discharges.
Subject(s)
Hippocampus/pathology , Neuronal Ceroid-Lipofuscinoses/pathology , Child , Epilepsy/pathology , Humans , Tripeptidyl-Peptidase 1ABSTRACT
Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wild-type allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. The derived linkage, loss of heterozygosity, and clinical data suggest that MCL and HLRCC are a single disease with a variable phenotype. The possibility that members of leiomyomatosis families are predisposed to renal cell cancer should be taken into account.
Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Leiomyomatosis/genetics , Neoplasms, Multiple Primary , Skin Neoplasms/genetics , Adult , Carcinoma, Renal Cell/pathology , Female , Genetic Linkage , Genetic Predisposition to Disease , Humans , Kidney Medulla/pathology , Kidney Neoplasms/pathology , Loss of Heterozygosity , Male , PedigreeABSTRACT
The majority of oocytes present in fetal ovaries are depleted before birth, and only about 400 will ovulate during the normal fertile life span. Studies on animals have shown that apoptosis is the mechanism behind oocyte depletion and follicular atresia. In the present study, we investigated the extent and localization of apoptosis in human fetal (aged 13-40 weeks) and adult ovaries. Furthermore, the expression of apoptosis-regulating proteins, bcl-2 and bax, and the relationship of transcription factor GATA-4 were studied. Apoptosis was found in ovarian follicles throughout fetal and adult life. During fetal development, apoptosis was localized mainly to primary oocytes and was highest between weeks 14-28, decreasing thereafter toward term. Expression of bcl-2 was observed only in the youngest fetal ovaries (weeks 13-14), and bax was present in the ovaries throughout the entire fetal period. In adult ovaries, apoptosis was detected in granulosa cells of secondary and antral follicles, and Bcl-2 and bax were expressed from primary follicles onwards. During fetal ovarian development, GATA-4 messenger RNA and protein were localized to the granulosa cells, with expression being highest in the youngest ovaries and decreasing somewhat toward term. The expression pattern of GATA-4 suggests that it may be involved in the mechanisms protecting granulosa cells from apoptosis from fetal to adult life. The results indicate that depletion of ovarian follicles in the human fetus occurs through intrinsic mechanisms of apoptosis in oocytes, and later in adult life the survival of growing follicles may be primarily determined by granulosa cell apoptosis.
Subject(s)
Apoptosis , DNA-Binding Proteins/analysis , Ovarian Follicle/physiology , Transcription Factors/analysis , Aging , Blotting, Northern , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Female , GATA4 Transcription Factor , Gestational Age , Granulosa Cells/chemistry , Granulosa Cells/cytology , Humans , Immunohistochemistry , In Situ Hybridization , Oocytes/cytology , Ovarian Follicle/embryology , Ovarian Follicle/growth & development , Ovary/chemistry , Ovary/cytology , Ovary/embryology , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins/physiology , Proto-Oncogene Proteins c-bcl-2/analysis , Proto-Oncogene Proteins c-bcl-2/physiology , RNA, Messenger/analysis , Transcription Factors/genetics , Transcription Factors/physiology , bcl-2-Associated X ProteinABSTRACT
Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.
Subject(s)
Base Pair Mismatch , DNA Repair/genetics , Microsatellite Repeats/genetics , Adaptor Proteins, Signal Transducing , Brain Neoplasms/genetics , Carrier Proteins , Child, Preschool , DNA/genetics , DNA/isolation & purification , Female , Glioma/genetics , Humans , MutL Protein Homolog 1 , Mutation , Neoplasm Proteins/genetics , Nuclear ProteinsABSTRACT
Although characterized by a highly variable phenotype and multiple genetic alterations, glioblastomas are considered monoclonal in origin. We here report on a 64-yr-old patient who developed a second glioblastoma in the left frontal lobe 10 yr after surgical resection of a glioblastoma of right frontal lobe. The first tumor contained 2 p53 mutations, in codon 213 (CGA-->TGA, Arg-->stop) and codon 306 (CGA-->TGA, Arg-->stop), further, 1 missense PTEN mutation (codon 257, TTC-->TTA, Phe-->Leu) and a silent PTEN mutation (codon 154, TTC-->TTT, Phe-->Phe). The second glioblastoma also contained multiple, but different mutations: p53 mutations in codons 158 (CGC-->CAC, Arg-->His) and 273 (CGT-->TGT, Arg-->Cys), and a PTEN mutation in codon 233 (CGA-->TGA, Arg-->Stop). Both neoplasms had a homozygous p16 deletion. The discordant pattern of mutations indicates that the second glioblastoma was not a recurrence but an independent second glioblastoma. The presence in these neoplasms of multiple mutations in tumor suppressor genes suggests the involvement of a novel disease mechanism but there was no indication of a DNA mismatch repair deficiency or of an inherited tumor syndrome.
Subject(s)
Glioblastoma/genetics , Glioblastoma/pathology , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/pathology , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 19/genetics , DNA Mutational Analysis , Frontal Lobe/diagnostic imaging , Frontal Lobe/pathology , Glioblastoma/diagnostic imaging , Humans , Immunohistochemistry , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasms, Second Primary/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancer can be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.
Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Leiomyoma/genetics , Uterine Neoplasms/genetics , Adult , Carcinoma, Renal Cell/complications , Chromosomes, Human , Female , Genetic Markers , Genetic Predisposition to Disease/genetics , Humans , Kidney Neoplasms/complications , Leiomyoma/classification , Leiomyoma/complications , Leiomyoma/pathology , Leiomyosarcoma/classification , Leiomyosarcoma/complications , Leiomyosarcoma/genetics , Male , Middle Aged , Pedigree , Phenotype , Uterine Neoplasms/classification , Uterine Neoplasms/complications , Uterine Neoplasms/pathologyABSTRACT
GATA-4 is a highly conserved transcription factor that plays a critical role in regulating embryonic morphogenesis and cellular differentiation. Given the emerging role of GATA-4 in the development and function of murine gonads, we have now studied its role in human testis. We find that GATA-4 is expressed from early human fetal testicular development to adulthood. This transcription factor is evident in Sertoli cells through fetal and postnatal development. Expression of GATA-4 in Sertoli cells peaks at 19-22 weeks gestation at the time of high circulating fetal FSH. In Leydig cells, GATA-4 is expressed during fetal period and after puberty, coinciding with the periods of active androgen synthesis in the testis; this suggests a link between GATA-4 and steroidogenesis. Also, fetal germ cells and prepubertal spermatogonia express GATA-4, and it is down-regulated in these cells after puberty. As hormonal regulation of GATA-4 in human testis was not possible to study directly, we used testicular samples from patients who had endocrine abnormalities or were hormonally treated. Testicular expression of GATA-4 in hCG-treated cryptorchidism does not differ from that in controls. In androgen resistance, GATA-4 expression in Sertoli and germ cells is weak or totally absent. GATA-4 protein is abundantly present in Sertoli and Leydig cell tumors, suggesting a relationship to tumorigenesis or tumor progression in somatic cell-derived testicular neoplasms.