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Marc Fellous

Publications and source records attributed to Marc Fellous.

26 records · Page 2Linked to original sources
PubMed2002

Aetiological diagnosis of male sex ambiguity: a collaborative study.

UNLABELLED: A collaborative study, supported by the Biomed2 Programme of the European Community, was initiated to optimise the aetiological diagnosis in genetic or gonadal males with intersex disorders, a total of 67 patients with external sexual ambiguity, testicular tissue and/or a XY karyotype. In patients with gonadal dysgenesis or true hermaphroditism, the incidence of vaginal development was 100%, a uterus was present in 60%; uni or bilateral cryptorchidism was seen in nearly all cases of testicular dysgenesis (99%) but in only 57% of true hermaphrodites. Mean serum levels of anti-mullerian hormone and of serum testosterone response to chorionic gonadotropin stimulation were significantly decreased in both conditions, by comparison with patients with unexplained male pseudohermaphroditism or partial androgen insensitivity (PAIS). Mutations in the androgen receptor, 90% within exons 2-8, were detected in patients with PAIS. Clinically, a vaginal pouch was present in 90%, cryptorchidism in 36%. In 52% of cases, no diagnosis could be reached, despite an exhaustive clinical and laboratory work-up, including routine sequencing of exons 2-8 of the androgen receptor. By comparison with PAIS, unexplained male pseudohermaphroditism was characterised by a lower incidence of vaginal pouch (55%) and cryptorchidism (22%) but a high incidence of prematurity/intrauterine growth retardation (30%) or mild malformations (14%). CONCLUSION: reaching an aetiological diagnosis in cases of male intersex is difficult because of the variability of individual cases. Hormonal tests may help to discriminate between partial androgen insensitivity and gonadal dysgenesis/true hermaphroditism but are of less use for differentiating from unexplained male pseudohermaphroditism. Sequencing of exons 2-8 of the androgen receptor after study of testosterone precursors following human chorionic gonadotrophin stimulation is recommended when gonadal dysgenesis and true hermaphroditism can be excluded.

Anti-Mullerian Hormone↗
PubMed2002

Molecular genetics of sex determination.

In humans, the choice between male or female development is genetically determined. Sex determination take place when the bipotential embryonic gonad becomes either testis or ovary. This process is directed by genes that have been discovered by genetic analysis of sex-reversed patients and confirmed by knockout experiments in mice. The testis-determining pathway is better known than the ovary pathway. SRY, a gene located on the Y chromosome, triggers a complex genetic cascade leading to testicular differentiation. In this cascade, two genes play a crucial role in male differentiation, SOX9 and FGF9, which contribute to testicular cord formation. However, only a minority of 46,XY sex-reversed patients can be explained by mutations in known genes such as SRY, SOX9, WTI, and SF1, suggesting that other genes influencing sex determination are yet to be discovered. In females, some rare genes that induce ovarian failure or female-to-male sex reversal have been found through gene-targeted inactivation in mice or positional cloning of mutations in humans and goats. In both sexes, genetic analysis of sex-reversed individuals (XX males, XX and XY hermaphrodites, and XY with complete or partial dysgenesis) remains an approach of choice to isolate new genes involved in sex determination.

Animals↗
PubMed2002

MHC class II-deficient tumor cell lines with a defective expression of the class II transactivator.

MHC class II expression defects have been evidenced in several human tumor cell lines originating from lung cancers or retinoblastoma. Accordingly, the mouse adenocarcinoma and fibrosarcoma cell lines, RAG and L(tk-), do not express I-A and I-E molecules even when treated with IFN-gamma. Here we show that fusion of both cell lines restores the inducible expression of MHC class II, thereby demonstrating that they present different and recessive alterations outside the MHC class II locus. CIITA, the MHC class II transactivator, controls the tissue-specific expression of MHC class II genes and creates the architecture of the transcriptional complex that binds to the MHC class II gene promoters. In L(tk-) cells, C2ta transcripts, expressed from the gene encoding CIITA, were indeed detected in severely limited amounts, with a defect in C2ta transcription initiation. In agreement we show here that the L(tk-) cell line does not express the CIITA protein. In contrast, in the RAG cell line, C2ta transcripts were expressed at normal levels, from the proper initiation site. The nucleotide sequencing of the CIITA cDNA from RAG did not reveal any mutation. However, the CIITA protein was not detected. These data evidence a new type of defect in a MHC class II-defective tumor cell line, as we show here that the alteration in the RAG cells occurs downstream of C2ta transcription. The RAG mutation might therefore reside in the C2ta transcript nuclear export or translation, or in the stability of the CIITA protein.

Animals↗
PubMed2002

[The genetics of sex determination].

The male sex determination controls the testis determination and differentiation. So far more than a dozen of gene have been characterised, including the primary Y male sex determinant: SRY gene. All the genes encode transcription factor except FDF9 which encodes a growth factor allowing mesonephritic cell to divide and migrate to the mesenchyme. All these gene products are sensitive in man (but not in the mouse model) to gene dosage: haplo-insufficiency and or duplication of these genes all lead to sex reversal. Today, we still do not know how their products are epistatic in the sex determining cascade. So far no ovary sex determining gene has been characterised.

Animals↗
PubMed2001

The Human Y Chromosome: The Biological Role of a "Functional Wasteland"

"Functional wasteland," "Nonrecombining desert" and "Gene-poor chromosome" are only some examples of the different definitions given to the Y chromosome in the last decade. In comparison to the other chromosomes, the Y is poor in genes, being more than 50% of its sequence composed of repeated elements. Moreover, the Y genes are in continuous decay probably due to the lack of recombination of this chromosome. But the human Y chromosome, at the same time, plays a central role in human biology. The presence or absence of this chromosome determines gonadal sex. Thus, mammalian embryos with a Y chromosome develop testes, while those without it develop ovaries (Polani, 1981). What is responsible for the male phenotype is the testis-determining SRY gene (Sinclair, 1990) which remains the most distinguishing characteristic of this chromosome. In addition to SRY, the presence of other genes with important functions has been reported, including a region associated to Turner estigmata, a gene related to the development of gonadoblastoma and, most important, genes related to germ cell development and maintenance and then, related with male fertility (Lahn and Page, 1997). This paper reviews the structure and the biological functions of this peculiar chromosome.

Journal Article↗
PubMedDate not supplied

Gonad development in Drash and Frasier syndromes depends on WT1 mutations.

The study of the gonads of 8 cases of Drash syndrome (6 ambiguous males, 2 females) and of 2 Frasier syndrome shows that WT1 mutations gives a dysgenetic testis which is the cause of the genital ambiguity observed at birth. By contrast the same mutations have no effect on ovary development giving normal females. However intron mutations in KTS with isoforms imbalance of WT1 proteins cause streak gonads with a female phenotype in XY patients. In consequence WT1 mutations are the cause of a spectrum of male genital malformations associated with glomerulonephritis and tumors. The absence of WT1 protein detection in sertoli cells shown by immunohistochemistry for 3 cases suggests an imprinting effect of the normal WT1 allele promotor rather than a low level of protein production. A caryotype is mandatory for a correct diagnosis.

Adolescent↗