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Stefano Cairo,
Carolina Armengol,
Aurélien De Reyniès,
Yu Wei,
Emilie Thomas,
Claire-Angélique Renard,
Andrei Goga,
Asha Balakrishnan,
Michaela Semeraro,
Lionel Gresh, [......],
François Plenat,
Dominique Zachar, Madeleine Joubert,
Janick Selves,
Dominique Pasquier,
Paulette Bioulac-Sage,
Michael Grotzer,
Margaret Childs,
Monique Fabre,
Marie-Annick Buendia
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Stefano Cairo,
Carolina Armengol,
Aurélien De Reyniès,
Yu Wei,
Emilie Thomas,
Claire-Angélique Renard,
Andrei Goga,
Asha Balakrishnan,
Michaela Semeraro,
Lionel Gresh, [......],
François Plenat,
Dominique Zachar, Madeleine Joubert,
Janick Selves,
Dominique Pasquier,
Paulette Bioulac-Sage,
Michael Grotzer,
Margaret Childs,
Monique Fabre,
Marie-Annick Buendia
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Stefano Cairo,
Carolina Armengol,
Aurélien De Reyniès,
Yu Wei,
Emilie Thomas,
Claire-Angélique Renard,
Andrei Goga,
Asha Balakrishnan,
Michaela Semeraro,
Lionel Gresh, [......],
François Plenat,
Dominique Zachar, Madeleine Joubert,
Janick Selves,
Dominique Pasquier,
Paulette Bioulac-Sage,
Michael Grotzer,
Margaret Childs,
Monique Fabre,
Marie-Annick Buendia
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ABSTRACT: Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.
Cancer cell 01/2009; 14(6):471-84. · 25.29 Impact Factor
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ABSTRACT: The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. Children with WAGR syndrome invariably have a constitutional chromosomal deletion at 11p13. WT1 haploinsufficiency is associated with a significant risk of Wilms tumor while PAX6 haploinsufficiency lead to aniridia, both genes located in the deleted region. The 46,XY patients with WAGR syndrome are often born with genital abnormalities such as cryptorchidism or hypospadias but more rarely ambiguous genitalia. To our knowledge, complete sex reversal has never been observed in WAGR syndrome patients. Here, we report on the clinical, cytogenetic, and molecular characterization of a child with WAGR syndrome and complete sex reversal. The young girl had female external and internal genitalia with normal uterus and fallopian tubes while the ovaries were not observed. Chromosomal analysis showed a 46,XY,del(11)(p12p14.1) karyotype. A 1-Mb resolution array CGH experiment estimated the size of the interstitial deletion at approximately 10 Mb encompassing WT1 and PAX6. The entire coding regions of WT1 and SRY have been sequenced and no mutation has been identified. Frasier syndrome (FS) and Denys-Drash syndrome (DDS) are two disorders associated with mutations in the WT1 gene. Complete sex reversal is a feature usually present in FS and sometimes in DDS, but until now never observed in WAGR syndrome. The present report suggests that these conditions may be considered as part of the spectrum of disease due to WT1 gene alterations.
American Journal of Medical Genetics Part A 12/2007; 143A(22):2692-5. · 2.39 Impact Factor
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Mireille Lacoste,
Yi Cai,
Liliane Guicharnaud,
Françoise Mounier,
Yves Dumez,
Raymonde Bouvier,
Frédérique Dijoud,
Marie Gonzales,
Jane Chatten,
Anne-Lise Delezoide, [......],
Anne Marie Frances,
Farida Daïkha-Dahmane,
Aurore Coulomb,
Thomas J Neuhaus,
Bernard Foliguet,
Pierre Chenal,
Pascale Marcorelles,
Jean Marie Gasc,
Pierre Corvol,
Marie Claire Gubler
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ABSTRACT: Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensin-converting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis.
Journal of the American Society of Nephrology 09/2006; 17(8):2253-63. · 9.66 Impact Factor
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Olivier Gribouval,
Marie Gonzales,
Thomas Neuhaus,
Jacqueline Aziza,
Eric Bieth,
Nicole Laurent,
Jean Marie Bouton,
François Feuillet,
Saloua Makni,
Hatem Ben Amar,
Guido Laube,
Anne-Lise Delezoide,
Raymonde Bouvier,
Frédérique Dijoud,
Elisabeth Ollagnon-Roman,
Joelle Roume, Madeleine Joubert,
Corinne Antignac,
Marie Claire Gubler
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ABSTRACT: Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.
Nature Genetics 10/2005; 37(9):964-8. · 35.53 Impact Factor
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Houda Karmous-Benailly,
Jelena Martinovic,
Marie-Claire Gubler,
Yoann Sirot,
Laure Clech,
Catherine Ozilou,
Joëlle Auge,
Nora Brahimi,
Heather Etchevers,
Eric Detrait, [......],
Anne-Lise Delezoide,
Marie-Odile Peter,
Ghislaine Plessis,
Brigitte Simon-Bouy,
Hélène Dollfus,
Martine Le Merrer,
Arnold Munnich,
Férechté Encha-Razavi,
Michel Vekemans,
Tania Attié-Bitach
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ABSTRACT: Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.
The American Journal of Human Genetics 04/2005; 76(3):493-504. · 10.60 Impact Factor
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ABSTRACT: 46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission. However, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male-to-male transmission. This kindred supports the involvement of at least one autosomal gene in non-syndromic 46,XY gonadal dysgenesis.
American Journal of Medical Genetics Part A 02/2003; 116A(1):37-43. · 2.39 Impact Factor
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ABSTRACT: We report on a fetus with multiple congenital anomalies including atypical lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, cleft palate, ventricular septal defect, and hypoplastic aortic arch. The initial routine chromosome study failed to detect any abnormality. Subtelomeres analysis by MLPA identified an 18q23 duplication inherited from its healthy father. We describe the anomalies identified and discuss diagnosis and the causability of this telomeric duplication.
European Journal of Medical Genetics 51(3):231-8. · 2.18 Impact Factor
