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Biomedical subjects

M Fellous

Publications and source records attributed to M Fellous.

At least 109 records · Page 6Linked to original sources
PubMed1992

A protein tyrosine kinase in the interferon alpha/beta signaling pathway.

The mutant human cell line 11.1 is unresponsive to interferon alpha. Here we describe the genetic complementation of this mutant and the identification and cloning of the wild-type gene that corrects the defect. Using transfection with genomic DNA in conjunction with a powerful back-selection, we isolated a cosmid that reverts the mutant phenotype of 11.1 cells. The cosmid encodes a single message whose level is greatly reduced in mutant cells. Complementary DNAs were cloned and found to be virtually identical to tyk2, a human mRNA encoding a non-receptor protein tyrosine kinase of previously unknown function. This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes.

Amino Acid Sequence↗
PubMed1992

[Sex genetics].

The sex gene SRY has recently been characterized after years of research during which the candidate genes HY and ZFY were excluded. SRY does have all the characteristics expected of the sex gene: it is located on chromosome Y of all mammals, including man; it is specifically expressed in male gonads during early embryonic development mutations and deletions have been found in 46,XY women with gonadal dysgenesis; the Sry gene is present in the vast majority of XX men and finally, transgenic experiments in the mouse have shown that Sry reverses the sex of XX mice. All this demonstrates that SRY is truly the sex gene, but some abnormalities of sex determination in humans remain shrouded in mystery. There are 46,XX men who do not carry the sex gene, and some 46,XX SRY positive true hermaphrodites in whose gonads ovarian and testicular tissues coexist. Finally, SRY is apparently normal in the majority of pure gonadal dysgenesis.

Crossing Over, Genetic↗
PubMed1992

A protein from Daudi cell line conditioned medium induces ovarian dysgenesis in Drosophila melanogaster.

From a medium in which Daudi cells had been grown, we isolated by HPLC a protein that caused ovarian abnormalities in adult females of Drosophila melanogaster when injected into preblastoderm embryos. This protein, whose apparent M(r) is between 30,000 and 50,000, was found to be a moderately polar compound which is heat stable and whose activity is destroyed by acidification. The protein is characteristic of medium conditioned from Daudi cells.

Animals↗
PubMed1992

XY sex reversal associated with a nonsense mutation in SRY.

Sex determination in humans is mediated through the expression of a testis-determining gene on the Y chromosome. In humans, a candidate gene for the testis-determining factor (TDF) that encodes a protein with a putative DNA-binding motif and has been isolated is termed SRY. Here we describe an XY sex-reversed female with pure gonadal dysgenesis who harbors a de novo nonsense mutation in the SRY open reading frame (SRY-orf). This single-basepair substitution results directly in the formation of a termination codon in the putative SRY DNA-binding motif, presumably leading to a nonfunctional gene product. This brings the number of reported XY sex-reversed females with de novo mutations in the known SRY-orf to three, each occurring in the putative DNA-binding domain. This provides further evidence to support SRY being TDF in humans and also indicates the functional importance of the putative DNA-binding domain of the SRY protein.

Base Sequence↗
PubMed1992

The sole presence of the testis-determining region of the Y chromosome (SRY) in 46,XX patients is associated with phenotypic variability.

Four cases of XX patients with testis development are reported. The aim of this study was to describe their clinical features and to see if there was any relationship between phenotypes and the presence of Y material. Several human Y-derived sequences including the SRY probe were used to analyze the DNA of the patients. Yp material including the pseudo-autosomal region and SRY was detected. The cases reported in this study confirm that XX true hermaphrodites cannot be distinguished from XX males on the basis of their genotypes. There is no relationship between clinical and anatomical phenotypes and the presence of Y material. SRY does not warrant a complete and normal testis differentiation. Although similar in some features with Klinefelter's syndrome patients, XX males exhibit specific clinical manifestations due to the lack of Y-specific genes.

Adolescent↗
PubMed1992

Familial case with sequence variant in the testis-determining region associated with two sex phenotypes.

The human Y chromosome encodes a testis-determining factor (TDF) which is responsible for initiating male sex determination. Recently a region of the Y chromosome (SRY) was identified as part of the TDF gene. We have identified a three-generation family (N) in which all XY individuals have a single base-pair substitution resulting in a conservative amino acid change in the conserved domain of the SRY open reading frame. Three individuals are XY sex-reversed females, and two are XY males. Several models are proposed to explain association between a sequence variant in SRY and two sex phenotypes.

Adolescent↗
PubMed1991

Human chromosome 16 encodes a factor involved in induction of class II major histocompatibility antigens by interferon gamma.

Interferon gamma (IFN-gamma) induces expression of class II major histocompatibility complex (MHC)-encoded antigens in immunocompetent cells. To gain further insight into the mechanism of this induction, we prepared somatic cell hybrids between different human cell lines and a murine cell line, RAG, that does not express murine class II MHC antigens before or after treatment with murine IFN-gamma. Some of the resulting cell hybrids express murine class II MHC antigens when treated with murine IFN-gamma. This inducible phenotype is correlated with the presence of human chromosome 16. It has been shown previously that the induction of class I MHC antigens by human IFN-gamma in human-rodent hybrids requires the presence of species-specific factors encoded by chromosome 6, which bears the gene for the human IFN-gamma receptor, and chromosome 21, whose product(s) is necessary for the transduction of human IFN-gamma signals. In this report, we show that the induction of murine class II MHC antigens by human IFN-gamma in the human-RAG cell hybrids requires, likewise, the presence of human chromosomes 6 and 21, in addition to chromosome 16. In some of these hybrids, when all three of these human chromosomes were present, induction of cell-surface HLA-DR antigens was also observed. Our results demonstrate that human chromosome 16 encodes a non-species-specific factor involved in the induction of class II MHC antigens by IFN-gamma.

Animals↗
PubMed1991

[Genetic factor of sex determination].

We have analyzed 40 cases of human XX male or XX true hermaphrodites negative for Y DNA sequences including ZFY. Among these patients we were able to demonstrate the existence of at least 3 mechanisms. 1) In one case a mosaïscism 46XY/46XX is limited to the gonad and only detected by PCR. 2) Familial cases compatible with the mutation of an autosomal (or pseudo-autosomal) down stream sex determining gene. 3) We finally observed 5 cases lacking ZFY meanwhile carrying Y specific sequences near to the pseudo-autosomal boundary, redifining the region where TDF must lie.

Animals↗
PubMed1990

Genetic evidence equating SRY and the testis-determining factor.

The testis-determining factor gene (TDF) lies on the Y chromosome and is responsible for initiating male sex determination. SRY is a gene located in the sex-determining region of the human and mouse Y chromosomes and has many of the properties expected for TDF. Sex reversal in XY females results from the failure of the testis determination or differentiation pathways. Some XY females, with gonadal dysgenesis, have lost the sex-determining region from the Y chromosome by terminal exchange between the sex chromosomes or by other deletions. If SRY is TDF, it would be predicted that some sex-reversed XY females, without Y chromosome deletions, will have suffered mutations in SRY. We have tested human XY females and normal XY males for alterations in SRY using the single-strand conformation polymorphism assay and subsequent DNA sequencing. A de novo mutation was found in the SRY gene of one XY female: this mutation was not present in the patient's normal father and brother. A second variant was found in the SRY gene of another XY female, but in this case the normal father shared the same alteration. The variant in the second case may be fortuitously associated with, or predisposing towards sex reversal; the de novo mutation associated with sex reversal provides compelling evidence that SRY is required for male sex determination.

Amino Acid Sequence↗
PubMed1990

A possible common origin of "Y-negative" human XX males and XX true hermaphrodites.

We have studied nine patients aged 1 month to 16 years with 46, XX karyotypes and testicular tissue. Some of these patients were followed through puberty. Phenotypically, two presented normal and seven abnormal external genitalia (AG). Among this latter group, four showed hypospadias and three true hermaphroditism (TH). The endocrine data were similar in all three groups: testosterone levels were within normal limits during puberty, decreasing in adulthood; gonadotrophin levels were above the control values at mid puberty. Histologies of the two sub groups of AG patients were identical up to 5 years of age and presented differences when compared with controls, regardless of the ovarian part of the ovotestis. However, in patients older than 8 years, germ cells disappeared and dysgenesis became obvious. In one patient, the ovarian zone of the gonad was detected only after complete serial sections of the removed gonad were examined. Southern blot analysis with Y-DNA probes displayed Y-specific material for the classic 46 XX males and a lack of such sequences for all patients with AG and TH. Based on these findings, we postulate that 46, XX males with AG and 46, XX TH may represent alternative manifestations of the same genetic defect. These data together with those concerning familial cases of 46, XX males with AG and 46, XX TH suggest an autosomally (or pseudoautosomally) determined mechanism.

Adolescent↗
PubMed1990

A 45,X male with molecular evidence of a translocation of Y euchromatin onto chromosome 1.

A 45,X complement was found in lymphocyte and fibroblast cultures of a male infant with severe growth and mental retardation and mild dysmorphism. Lymphocyte DNA from this patient was found to contain Yp chromosome sequences. In situ hybridization (ISH) with the 50f2 probe led to a clear assignment of euchromatic material on the short arm of chromosome 1. This observation and others from the literature argue in favour of the conclusion that all 45,X males are probably either the result of undetected mosaicism or are carriers of Y translocated material.

Child, Preschool↗
PubMed1990

Investigation of the ZFY gene in XX true hermaphroditism and Swyer syndrome.

Four patients with 46,XX true hermaphroditism and one patient with 46,XY pure gonadal dysgenesis (Swyer syndrome) were analyzed with a Y chromosome-derived probe that detects a specific fragment on the short arm of the Y chromosome in the putative testicle-determining region and also a fragment on the short arm of the X chromosome. Normal males and females, an individual with Turner syndrome, and patients with various causes of anomalous gonadal differentiation accompanied by cytogenetically present Y chromosome were used as controls. The Y-specific fragment was not detected in any of the persons with 46,XX true hermaphroditism. However, this fragment was positive in the 46,XY female and in all Y-bearing patients. Cytogenetic and molecular absence of the ZFY sequence in 46,XX true hermaphrodites calls for explanations other than the classic embryogenic theory. The absence of testicular differentiation in the ZFY-positive XY female evidences functionally altered sex determination or, alternatively, defective gonadal receptors.

Adolescent↗
PubMed1990

Y chromosome DNA polymorphisms in human populations: differences between Caucasoids and Africans detected by 49a and 49f probes.

Several Y-specific TaqI fragments are recognized by 49a and 49f probes in human male DNA digests. The occurrence of polymorphic variations in six of these fragments (A, B, C, D, F and I) has recently been reported, providing a potentially powerful tool for the study of the population genetics of the Y chromosome. The 49a-49f/TaqI polymorphisms were studied in 121 Africans (Senegal and Cameroon) and 125 Caucasians (Italy). In addition to the variability described already, four new bands were observed. Moreover, three patterns were found in which bands constantly present so far (G, O and H-P-R) were missing. At variance with previously reported findings, the coexistence of two different fragments of the same 'allelic' series (A or D) was frequently observed in the Italian sample (10.4%). For some of these 'double-banded' patterns their holoandric transmission could be demonstrated by family studies. In the light of these new findings, the hypothesis of A or D fragments being allelic forms, as advanced by the authors who first described these polymorphisms, has to be reconsidered. A total of 34 haplotypes were encountered, 22 of which are new. The Africans tested all lack C and D fragments. Moreover, about 80% of them are characterized by a band, A1, not present in the Italian group. The combination of A1C0D0 could therefore be a powerful genetic marker of paternal African ancestry. This combination occurs in five haplotypes, one of which, haplotype IV, accounts for 68% of the African sample. In contrast with the results of the mtDNA analysis on the same population samples, the degree of variability displayed by the Y chromosome sequences appears to be much lower in Africans than in Caucasians.

Africa↗
PubMed1990

[Diagnosis of the sex of bovine embryos using molecular biology].

Thanks to a bovine genomic library enriched with Y chromosome-specific sequences, a probe specific to this chromosome of genera Bos and Bison and repeated on about 2,000 copies in the male genome was isolated. To be compatible with embryo transfer and/or freezing, sex determination has to be done on a 10-20 cell embryo biopsy from a day-7 bovine blastocyst. The in situ hybridization with biotinylated BC 1.2 probe and immunocytochemical revelation permitted the visualization of the hybridization signal on the nucleus of each cell. Because of the numerous steps required, this technique was difficult to apply routinely. For that reason we worked out the polymerase chain reaction technique. From the BC 1.2 sequence, we determined several oligonucleotide primers and probes with the aim of amplifying the Y chromosome-specific sequences. This technique, which is easy to perform and to automate, enabled us to obtain a strong male-specific hybridization signal on genomic DNA and embryo cells.

Animal Husbandry↗
PubMed1989

TNF stimulates expression of mouse MHC class I genes by inducing an NF kappa B-like enhancer binding activity which displaces constitutive factors.

We have dissected the mouse H-2Kb gene promoter in order to define the sequences responsible for induction by tumour necrosis factor (TNF-alpha). An enhancer element (-187 to -158) composed of two imperfect direct palindromic repeats has been shown to be necessary and sufficient for TNF-alpha induction of a heterologous promoter. A multimer of either repeat is also responsive, while a single copy is not: this is the situation in the beta 2-microglobulin (beta 2-m) promoter which contains a single palindrome and does not respond to TNF-alpha. We had previously found that the two repeats can bind a factor named KBF1. We show here that in the uninduced state the transcription factor AP2 binds to the interpalindromic region, while in TNF-treated cells an NF kappa B-like activity is induced which displaces both KBF1 and AP2 and binds to the two palindromes. This strongly suggests that induction of an NF kappa B-like activity is responsible for TNF-alpha stimulation of mouse MHC class I genes.

Animals↗