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Biomedical subjects

G Camerino

Publications and source records attributed to G Camerino.

At least 19 recordsLinked to original sources
PubMed2001

Frasier syndrome with childhood-onset renal failure.

BACKGROUND: The Wilms' tumour 1 (WT1) gene encodes a protein which is believed to exert transcriptional and tumour-suppressor activities. Mutations of this gene have occasionally been associated with Wilms' tumour (<15% of cases) and, more consistently, with three syndromes characterized by urogenital abnormalities (WAGR, Denys-Drash and Frasier syndrome). SUBJECT/METHOD: A 25-year-old phenotypic female with a 46,XY karyotype presented with amenorrhoea. An ultrasound scan showed streak gonads and a rudimentary uterus. The patient had a history of post-streptococcal glomerulonephrosis, when aged 4 years, which had rapidly progressed to kidney failure, requiring transplantation at age 8. RESULT: Frasier syndrome was suspected and confirmed by genetic analysis. In fact, direct sequencing of the PCR product of the intron 9 donor splice site revealed a substitution of guanine for adenine in position +5. CONCLUSION: Besides being one of the few Frasier syndrome cases to be genetically characterized, this case is interesting because of the unusually early-onset renal failure.

Adult↗
PubMed2001

DAX-1, an "antitestis" gene.

The DAX-1 gene has been involved in the dosage sensitive sex reversal (DSS) phenotype, a male-to-female sex-reversal syndrome due to the duplication of a small region of human chromosome Xp21. Dax-1 and Sry have been shown to act antagonistically in the mouse system, where increasing expression of the former leads to female development and increasing activity of the latter to male development. Although these data strongly implicate DAX-1 in sex determination, the mouse and human proteins appear to behave differently. Absence of DAX-1 is responsible for adrenal hypoplasia congenita, a human inherited disorder characterized by adrenal insufficiency and hypogonadotropic hypogonadism. Unlike human patients, Dax-1-deficient XY mice have normal levels of corticotropins and adrenal hormones but are sterile. Dax-1-deficient females are fertile. The DAX-1 protein, an unusual member of the nuclear hormone receptor, may act as a transcriptional repressor. It has been shown to both repress transcriptional activators by direct protein-protein interactions and to bind DNA hairpin structures and repress target genes.

Adrenal Insufficiency↗
PubMed2000

A new submicroscopic deletion that refines the 9p region for sex reversal.

Male to female sex reversal has been described in patients with deletions of chromosome 9p, and a region critical for sex reversal has been localized to p24.3, at the tip of the chromosome (TD9). It was proposed that the sex reversal may arise by haploinsufficiency for a gene localized to the minimum deletion. The 9p24.3 genes DMRT1 and DMRT2 are the favorite TD9 candidates to date, in virtue of their sequence similarity to doublesex and mab-3, sexual regulators in Drosophila and Caenorhabditis elegans, respectively. The hypothesis of sex reversal by combined haploinsufficiency for the two genes was put forward to explain the lack of mutations in either gene in XY sex-reversed females. Here we describe a XY sex-reversed patient carrying a novel 9p deletion that extends over less than 700 kb of genomic DNA. This region defines the smallest interval for sex reversal found to date. DMRT1 and DMRT2 map outside this region. Our data do not support the hypothesis of combined haploinsufficiency for DMRT1 and DMRT2. Nevertheless, DMRT1 localizes very close to the deletion breakpoint and has a pattern of expression compatible with a role in sex determination. It therefore remains a candidate gene for 9p sex reversal.

Amino Acid Sequence↗
PubMed2000

The expression pattern of a mouse doublesex-related gene is consistent with a role in gonadal differentiation.

The signal for somatic sex determination in mammals, Caenorhabditis elegans and Drosophila melanogaster is chromosomal, but the overall mechanisms do not appear to be conserved between the phyla. However it has been found quite recently that the C. elegans sex-determining gene Mab-3 contains a domain highly homologous to the Drosophila sex-determining gene doublesex (dsx) and shares a similar role. These data suggest that at least some aspects of the regulation of sex determination might be conserved. In humans, a doublesex-related gene (DMRT1) was identified at less than 30 kb from the critical region for sex reversal on chromosome 9p24 (TD9). In order to get insights into the role of DMRT1 in sex determination/differentiation, we have isolated DMRT1 mouse homologue (Dmrt1) and analysed its expression pattern. The gene is expressed in the genital ridges of both sexes during the sex-determining switch and it shows male/female dimorphism at late stages of sex differentiation.

Amino Acid Sequence↗
PubMed1999

DAX-1, an 'antitestis' gene.

The DAX-1 gene has been involved in the dosage sensitive sex reversal (DSS) phenotype, a male-to-female sex-reversal syndrome due to the duplication of a small region of human chromosome Xp21. Dax-1 and Sry have been shown to act antagonistically in the mouse system, where increasing expression of the former leads to female development and increasing activity of the latter to male development. Although these data strongly implicate DAX-1 in sex determination, the mouse and human proteins appear to behave differently. Absence of DAX-1 is responsible for adrenal hypoplasia congenita, a human inherited disorder characterized by adrenal insufficiency and hypogonadotropic hypogonadism. Unlike human patients, Dax-1-deficient XY mice have normal levels of corticotropins and adrenal hormones but are sterile. Dax-1-deficient females are fertile. The DAX-1 protein, an unusual member of the nuclear hormone receptor, may act as a transcriptional repressor. It has been shown to both repress transcriptional activators by direct protein-protein interactions and to bind DNA hairpin structures and repress target genes.

Adrenal Glands↗
PubMed1999

Combined hypothalamic-pituitary-gonadal defect in a hypogonadic man with a novel mutation in the DAX-1 gene.

We have studied a 20-yr-old male patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism (HH) due to a C to A transversion at nucleotide 825 in the DAX-1 gene, resulting in a stop codon at position 197. The same mutation was detected in his affected first cousin (adrenal hypoplasia congenita and HH) and in a heterozygous state in their carrier mothers. The patient had had acute adrenal insufficiency at the age of 2 yr and 6 months, bilateral cryptorchidism corrected surgically at the age of 12 yr, and failure of spontaneous puberty. Plasma testostereone (T) was undetectable (<0.30 nmol/L), gonadotropin levels were low (LH, <0.4 IU/L; FSH, 1.5 IU/L) and not stimulated after i.v. injection of 100 microg GnRH. The endogenous LH secretory pattern was apulsatile, whereas free alpha-subunit (FAS) levels depicted erratic pulses, suggesting an incomplete deficiency of hypothalamic GnRH secretion. During i.v. pulsatile GnRH administration (10 microg/pulse every 90 min for 40 h), each GnRH pulse induced a LH response of low amplitude (0.54 +/- 0.05 UI/L), whereas mean LH (0.45 +/- 0.01 IU/L) and FAS (63 +/- 8 mU/L) levels remained low. Amplitude of LH peaks (0.83 +/- 0.09 IU/L), mean LH (0.53 +/- 0.02 IU/L), and FAS (161 +/- 18 mU/L) levels increased (P < 0.01), whereas the T concentration remained low (0.75 nmol/L) when the pulsatile GnRH regimen was raised to 20 microg/pulse for a 40-h period, suggesting a partial pituitary resistance to GnRH. Thereafter, plasma T levels remained in prepubertal value after three daily im injections of 5000 IU hCG (3.6 nmol/L) and after 1-yr treatment with weekly i.m. injections of 1500 IU hCG (1.2 nmol/L), implying Leydig cell resistance to hCG. The patient had a growth spurt, bone maturation, progression of genital and pubic hair stages, and normalization of plasma T level (15.8 nmol/L) after a 12-month treatment with twice weekly injections of hCG and human menopausal gonadotropin (75 IU International Reference Preparation 2) preparations, suggesting that, in presence of FSH, a Sertoli cell-secreted factor stimulated Leydig cell production of T. In conclusion, we report a novel mutation in the DAX-1 gene in patients with AHC and HH. Our results suggest that the hypogonadism is due to a combined hypothalamic-pituitary-gonadal defect and imply that the DAX-1 gene may play a critical role in human testicular function.

Base Sequence↗
PubMed1998

Dax1 antagonizes Sry action in mammalian sex determination.

DAX1, which encodes an unusual member of the nuclear hormone-receptor superfamily, is a gene that may be responsible for a sex-reversal syndrome in humans, referred to as dosage-sensitive sex reversal, in which XY individuals carrying duplications of Xp21, part of the small arm of the X chromosome, develop as females. XY mice carrying extra copies of mouse Dax1 as a transgene show delayed testis development when the gene is expressed at high levels, but do not normally show sex reversal. Complete sex reversal occurs, however, when the transgene is tested against weak alleles of the sex-determining Y-chromosome gene Sry. These results show that DAX1 is largely, if not solely, responsible for dosage-sensitive sex reversal and provide a model for early events in mammalian sex determination, when precise levels and timing of gene expression are critical.

Animals↗
PubMed1997

The candidate sex-reversing DAX1 gene is autosomal in marsupials: implications for the evolution of sex determination in mammals.

The human X-linked DAX1 gene was cloned from the region of the short arm of the human X found in duplicate in sex-reversed Xdup Y females (E. Zanaria et al., 1994, Nature 372: 635-641). DAX1 is suggested to be required for ovarian differentiation and to play an important role in mammalian sex determination or differentiation pathways. Its proposed dose-dependent effect on sexual development suggests that DAX1 could represent an evolutionary link with an ancestral sex-determining mechanism that depended on the dosage of an X-linked gene. Furthermore, DAX1 could also represent the putative X-linked switch gene, which independently controls sexual dimorphisms in marsupial mammals in an X-dose-dependent manner (D.W. Cooper et al., 1993, Semin. Dev. 4: 117-128). If DAX1 has a present role in marsupial sexual differentiation or had an ancestral role in mammalian sex determination, it would be expected to lie on the marsupial X chromosome, despite the autosomal localization of other human Xp genes. We therefore cloned and mapped the DAX1 gene in the tammar wallaby (Macropus eugenii). DAX1 was located on wallaby chromosome 5p near other human Xp genes, indicating that it was originally autosomal and that it is not involved in X-linked dose-dependent sex determination in an ancestral mammal nor in marsupial sexual differentiation.

Amino Acid Sequence↗
PubMed1996

Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function.

Duplications of a chromosome Xp21 locus DSS (Dosage Sensitive Sex reversal) are associated with male to female sex reversal. An unusual member of the nuclear hormone receptor superfamily, DAX1, maps to the DSS critical region and is responsible for X-linked adrenal hypoplasia congenita. Here we describe the isolation of the mouse Dax1 gene and its pattern of expression during development. Expression was detected in the first stages of gonadal and adrenal differentiation and in the developing hypothalamus. Moreover, Dax1 expression is down-regulated coincident with overt differentiation in the testis, but persists in the developing ovary. Comparison of the predicted protein products of the human and mouse genes show that specific domains are evolving rapidly. Our results suggest a basis for adrenal insufficiency and hypogonadotropic hypogonadism in males affected by adrenal hypoplasia congenita and are consistent with a role for DAX1 in gonadal sex determination.

Adrenal Glands↗
PubMed1996

Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development.

Mutations of the orphan nuclear receptors, steroidogenic factor 1 (SF-1) and DAX-1, cause complex endocrine phenotypes that include impaired adrenal development and hypogonadotrophic hypogonadism. These similar phenotypes suggest that SF-1 and DAX-1 act in the same pathway(s) of endocrine development. To explore this model, we now compare directly their sites of expression. In mouse embryos, SF-1 expression in the urogenital ridge and brain either preceded or coincided with Dax-1 expression, with coordinate expression thereafter in the adrenal cortex, testis, ovary, hypothalamus, and anterior pituitary. The striking colocalization of SF-1 and Dax-1 supports the model that they are intimately linked in a common pathway of endocrine development. The slightly earlier onset of SF-1 expression and its ability to bind specifically to a conserved sequence in the Dax-1 5'-flanking region suggested that SF-1 may activate Dax-1 expression. However, promoter activity of Dax-1 5'-flanking sequences did not require this potential SF-1-responsive element, and Dax-1 expression was unimpaired in knockout mice lacking SF-1, establishing that SF-1 is not required for Dax-1 gene expression in these settings. Although the precise mechanisms remain to be established and may be multifactorial, our results strongly suggest that these two orphan nuclear receptors interact in a common pathway of endocrine development.

Animals↗
PubMed1995

Xp duplications and sex reversal.

Male to female sex reversal has been observed in individuals with duplications of the short arm of the X chromosome. The study of Xp duplicated patients demonstrated that sex reversal results from the presence of two active copies of the DSS (dosage sensitive sex reversal) locus. A double dosage of DSS disrupts testis formation whereas its absence is compatible with a male phenotype, suggesting a role for DSS in ovarian development and as a link between ovary and testis formation. DSS was localized to a 160 kb region of Xp21, overlapping the adrenal hypoplasia congenita locus. The search for expressed sequences in the DSS critical region led to the identification of two types of genes: the DAM family and DAX-1, an atypical member of the nuclear receptor superfamily. Although no function is currently known for DAM genes, functional deficiency for DAX-1 has been shown to be responsible for adrenal hypoplasia congenita and hypogonadotropic hypogonadism. The search for the DSS gene(s) is still open and both the DAM genes and DAX-1 represent DSS candidate genes.

Adrenal Insufficiency↗
PubMed1995

A family of rapidly evolving genes from the sex reversal critical region in Xp21.

Patients with an intact SRY gene and duplications of portions of Xp21 develop as phenotypic females. We have recently mapped this sex reversal locus, DSS, to a 160-kb region of Xp21 that includes the adrenal hypoplasia congenita locus. To clone the gene(s) underlying DSS and AHC, we isolated expressed sequences from the region. Here we describe the characterization of two related genes. DAM10 and DAM6, expressed in adult testis and lung tumors. The predicted DAM10 and DAM6 proteins are 66% identical and are both highly similar to the MAGE family of tumor-associated antigens and to mouse necdin. Genes belonging to the MAGE superfamily, DAMs, MAGEs, and necdin, are likely to have originated from a common ancestor and to be subject to an unusually rapid evolution. The tumor-restricted expression of DAM proteins and their structural similarity to MAGE genes suggest that DAM peptides may be targets for active immunotherapy in lung cancer patients.

Adult↗
PubMed1992

Three DNA markers for hypophosphataemic rickets.

This paper presents three markers, 16D/E, pHMAI (DXS208), and CRI-L1391 (DXS274), that show close linkage for X-linked hypophosphataemic rickets (HYP). DXS274 is closely linked to HYP (theta max = 0.00, Zmax = 4.20), and DXS41 (99.6), (theta max = 0.00, Zmax = 5.20). Marker 16D/E maps distal to the disease locus (theta max = 0.05, Zmax = 3.11). The pHMAI probe recognises the same restriction fragment length polymorphism (RFLP) as 99.6. Multipoint analysis suggests that the most probable order of loci is Xpter-(DXS43, 16D/E)-HYP-DXS274-(DXS208, DXS41)-Xcen. The location of DXS274 distal to HYP cannot be excluded, as no recombinants were observed between DXS274 and HYP, or between DXS274 and DXS41/DXS208. One of the families contains a large number of recombinants, four of which are double recombinants. This most probably means that the disease in this family maps elsewhere on the X chromosome or on an autosome, indicating locus heterogeneity.

Blotting, Southern↗
PubMed1992

The gene for X-linked Kallmann syndrome: a human neuronal migration defect.

A new gene from the distal short arm of the human X chromosome has recently been cloned and characterized. Mutations in this gene lead to the neuronal migration defect observed in Kallmann syndrome. Although there is no direct proof for the involvement of this gene in neuronal migration, significant similarities between its predicted protein product and neural adhesion molecules have been found. X-linked Kallmann syndrome represents the first example in vertebrates of a neuronal migration defect for which the gene has been isolated.

Cell Movement↗
PubMed1992

Kallmann syndrome due to a translocation resulting in an X/Y fusion gene.

The X-linked Kallmann syndrome gene was recently cloned and homologous sequences of unknown functional significance identified on the Y chromosome. We now describe a patient with Kallmann syndrome carrying an X;Y translocation resulting from abnormal pairing and precise recombination between the X-linked Kallmann syndrome gene and its homologue on the Y. The translocation created a recombinant, non-functional Kallmann syndrome gene identical to the normal X-linked gene with the exception of the 3' end which is derived from the Y. Our findings indicate that the 3' portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region, although a 'position' effect remains a formal possibility.

Amino Acid Sequence↗
PubMed1992

Identification of novel RFLPs in the vicinity of CpG islands in Xq28: application to the analysis of the pattern of X chromosome inactivation.

Probes for CpG islands were cloned from the distal long arm of the human X chromosome; three of them were found to be polymorphic. A HindIII RFLP was identified by the probe 2-25 (DXS606), and it was mapped to the Xq27-Xq28 boundary. Probes 2-19 (DXS605) and 2-55 (DXS707), which identify EcoRI and MspI polymorphisms, respectively, have been mapped to the distal part of Xq28, in the G6PD-RCP/GCP gene region. Probe 2-19 has been further localized about 16 kb from the 3' end of the G6PD gene. The new RFLPs may be useful for the precise mapping of the many disease genes localized in this part of the human X chromosome. Probe 2-19 is highly informative, and it has been studied in greater detail. Using the methylation-sensitive rare-cutter enzyme EagI in conjunction with the polymorphic EcoRI site, we were able to demonstrate that the RFLP may be used both to study randomness of X chromosome inactivation and for carrier detection in X-linked syndromes where nonrandom X inactivation occurs. It is conceivable that the combined use of 2-19 and of the probes described so far (pSPT-PGK and M27 beta) will make analysis of X inactivation feasible in virtually every female.

Alleles↗
PubMed1991

A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.

Kallmann's syndrome (clinically characterized by hypogonadotropic hypogonadism and inability to smell) is caused by a defect in the migration of olfactory neurons, and neurons producing hypothalamic gonadotropin-releasing hormone. A gene has now been isolated from the critical region on Xp22.3 to which the syndrome locus has been assigned: this gene escapes X inactivation, has a homologue on the Y chromosome, and shows an unusual pattern of conservation across species. The predicted protein has significant similarities with proteins involved in neural cell adhesion and axonal pathfinding, as well as with protein kinases and phosphatases, which suggests that this gene could have a specific role in neuronal migration.

Base Sequence↗