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C Antignac

Publications and source records attributed to C Antignac.

At least 19 recordsLinked to original sources
PubMed2006

[Ocular manifestations associated with nephronophthisis and genetic study in three Tunisian families].

PURPOSE: Nephronophthisis is a familial interstitial nephropathy with an autosome recessive mode of transmission. In some cases, it is associated with ocular manifestations such as retinitis pigmentosa in Senior-Løken syndrome. We report ocular abnormalities and genetic results in three affected Tunisian families. PATIENTS AND METHODS: Twenty-two members of these three families underwent a complete ophthalmologic examination (visual acuity, slit lamp biomicroscopy, ophthalmoscopy, and retinal electrophysiology). For genetic study, all individuals were genotyped and underwent a genomic sequence. RESULTS: Twenty-two subjects, nine of whom presented nephronophthisis, were included in this study. Retinitis pigmentosa was found in three cases. Our genetic study demonstrated that patients belonging to family 1 had homozygous deletions in NPHP1, all affected individuals from family 3 were linked to NPHP4 and presented a deletion in exons 2 and 3. Results are pending for patients in family 2. CONCLUSION: Senior-Løken syndrome is a rare hereditary disease that combines familial juvenile nephronophthisis and retinitis pigmentosa. This association was described in the literature in 39%-43% of cases. In our study, it was approximately 33% of cases. The genetic study can sometimes obviate the need for renal puncture, especially when the homozygous deletion of NPHP1 gene is confirmed.

Adolescent↗
PubMed2005

[Immunohistochemistry contribution in Alport syndrome diagnosis].

UNLABELLED: Alport syndrome (AS) is an hereditary disease characterised by the association of progressive hematuria nephritis. The diagnosis is based on clinical genetic and ultrastructural findings. Nowadays, immunohistochemical technique is of great interest. It enables us to analyze the distribution of the different chains of the type IV collagen in renal basement membrane (RBM) and epidermal basement membrane (EBM) which appeared to be abnormal in 70% of cases. METHODS: We report a prospective study of five families affected with AS. Six patients were investigated by immunohistochemical studies of kidney (3 cases) and skin (6 cases) frozen specimens. Monoclonal antibodies recognizing the collagenous domain of alpha1 (MAB1), alpha3 (MAB3) and alpha5 (MAB5) chains of type IV collagen were used. Two methods were performed: direct immunofluorescence and immunohistochemical (ultravision) analysis. RESULTS: The different chains distribution of type IV collagen in the EBM and RBM was normal in four cases (4 men), abnormal in two patients (1 man and woman). Based on the clinical, genetical and immunohistochemical findings we established three transmission modes: autosomal recessive in two families, dominant X linked in two other familiales, and autosomal dominant in one family. CONCLUSION: Immunohistochemical studies is a simple technique of an easy interpretation accomplished on kidney frozen specimen, or even on a simple cutaneous biopsy. It could be very useful for the diagnosis and enables us in addition to determine the mode of transmission of AS.

Adolescent↗
PubMed2005

Molecular basis of steroid-resistant nephrotic syndrome.

The identification of the underlying gene defect in some cases of steroid resistant nephrotic syndrome (SRNS) has recently led to a critical breakthrough in the understanding of the pathogenesis of nephrotic syndromes. The more severe form of hereditary nephrotic syndromes is the congenital nephrotic syndrome of the Finnish type (CNF). The causative gene, NPHS1, encodes a novel protein, nephrin which is a transmembrane protein belonging to the immunoglobulin superfamily specifically expressed in the podocyte at the slit diaphragm. Using a positional cloning approach, our group identified a gene, NPHS2, involved in a specific entity of familial SRNS characterized by early onset, complete steroid-resistance, rapid progression to ESRD and no recurrence after renal transplantation. NPHS2 encodes a novel membrane protein named podocin localized at the cytoplasmic part of the slit diaphragm. Familial autosomal dominant cases of primary FSGS have been described in adulthood. Two corresponding genes have been mapped to date, one to 19q13 and the second to 11q21-22. The former has been identified as ACTN4, the gene encoding the actin-binding protein, a-actinin 4. Other genes involved in the slit-diaphragm or the nephrotic syndrome are CD2-associated protein (CD2AP), FAT1, WT1, LMX1B, SMARCAL1. Altogether, these data demonstrate the pivotal role of the podocyte in the development and the maintenance of the glomerular filtration barrier and the crucial role of the genetic factors in the development of SRNS.

Actinin↗
PubMed2001

Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter.

Cystinosis is an inherited lysosomal storage disease characterized by defective transport of cystine out of lysosomes. However, the causative gene, CTNS, encodes a seven transmembrane domain lysosomal protein, cystinosin, unrelated to known transporters. To investigate the molecular function of cystinosin, the protein was redirected from lysosomes to the plasma membrane by deletion of its C-terminal GYDQL sorting motif (cystinosin-DeltaGYDQL), thereby exposing the intralysosomal side of cystinosin to the extracellular medium. COS cells expressing cystinosin-DeltaGYDQL selectively take up L-cystine from the extracellular medium at acidic pH. Disruption of the transmembrane pH gradient or incubation of the cells at neutral pH strongly inhibits the uptake. Cystinosin-DeltaGYDQL is directly involved in the observed cystine transport, since this activity is highly reduced when the GYDQL motif is restored and is abolished upon introduction of a point mutation inducing early-onset cystinosis. We conclude that cystinosin represents a novel H(+)-driven transporter that is responsible for cystine export from lysosomes, and propose that cystinosin homologues, such as mammalian SL15/Lec35 and Saccharomyces cerevisiae ERS1, may perform similar transport processes at other cellular membranes.

Amino Acid Motifs↗
PubMed2001

The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif.

Cystinosis is a lysosomal transport disorder characterized by an accumulation of intra-lysosomal cystine. Biochemical studies showed that the lysosomal cystine transporter was distinct from the plasma membrane cystine transporters and that it exclusively transported cystine. The gene underlying cystinosis, CTNS, encodes a predicted seven-transmembrane domain protein called cystinosin, which is highly glycosylated at the N-terminal end and carries a GY-XX-Phi (where Phi is a hydrophobic residue) lysosomal-targeting motif in its carboxyl tail. We constructed cystinosin-green fluorescent protein fusion proteins to determine the subcellular localization of cystinosin in transfected cell lines and showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes. Deletion of the GY-XX-Phi motif resulted in a partial redirection to the plasma membrane as well as sorting to lysosomes, demonstrating that this motif is only partially responsible for the lysosomal targeting of cystinosin and suggesting the existence of a second sorting signal. A complete relocalization of cystinosin to the plasma membrane was obtained after deletion of half of the third cytoplasmic loop (amino acids 280-288) coupled with the deletion of the GY-DQ-L motif, demonstrating the presence of the second signal within this loop. Using site-directed mutagenesis studies we identified a novel conformational lysosomal-sorting motif, the core of which was delineated to YFPQA (amino acids 281-285).

Amino Acid Sequence↗
PubMed2001

Benign familial hematuria associated with a novel COL4A4 mutation.

We describe a father and three offspring with hematuria. The father and one girl also complained of flank pain. Renal function tests and ophthalmological examinations were normal in all. The father had very mild neural deafness. The renal biopsy samples of two affected siblings showed changes compatible with thin basement membrane disease. Genetic analysis revealed a novel missense mutation in exon 32 of COL4A4 to be responsible for the phenotype in this family. We suggest that thin basement membrane disease may have overlapping clinical features with other causes of hematuria; genetic analysis may help in the differential diagnosis and help us further understand the disease processes.

Adolescent↗
PubMed2001

[Cerebellar vermis hypoplasia with extracerebral involvement (retina, kidney, liver): difficult to classify syndromes].

UNLABELLED: Congenital cerebellar vermis hypoplasias diversely associated with retinopathy, nephropathy and hepatopathy are rare syndromes of uncertain nosology. We report three new cases. CASE REPORTS: Case 1. A 3-month-old boy presented a brief nystagmus. At the age of 2 years, he had facial dysmorphia, hypotonia, ataxia, ocular motor apraxia and neurodevelopmental impairment with cerebellar vermis hypoplasia. The electroretinogram showed asymptomatic retinal involvement. At the age of 6 years, he developed chronic renal failure. The diagnosis of familial juvenile nephronophthisis was made by detection of a large homozygous deletion of the NPH1 region. Case 2. A term newborn boy presented apnea, tachypnea, hypotonia, nystagmus, ptosis, lack of visual contact and hepatomegaly. He had facial dysmorphia, bilateral optic coloboma with chorioretinal dysplasia and cerebellar vermis hypoplasia. There were cysts in the kidneys with increased echogenicity and lack of demarcation between the pyramids and the cortex. The liver was hyperechoic with fibrosis. At the age of 15 months, the child had severe developmental delay. He had bouts of fever. A search for a large homozygous deletion of the NPH1 region was negative. Case 3. A term newborn girl presented difficulty to suck, cyanosis, hypotonia and ptosis. Later, the child had a developmental delay. At the age of 6 years, she developed chronic renal failure (nephronophthisis). At the age of 23 years, she presented divergent strabismus, ataxia, mental retardation, slow ocular pursuit and facial dysmorphia. The neuroimaging showed a cerebellar vermis hypoplasia. A search for a large homozygous deletion of the NPH1 region was negative. CONCLUSION: The diagnosis of cerebellar vermis hypoplasia requires searching for retina, kidney and liver involvement. The large homozygous deletion of the NPH1 region has to be investigated if typical familial juvenile nephronophthisis is associated. Because cerebellar vermis hypoplasia with extracerebral involvements (retina, kidney, liver) is part of many different closely related syndromes, a clear molecular classification is necessary for accurate genetic counselling and an early prenatal diagnosis.

Abnormalities, Multiple↗
PubMed2001

Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.

Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself.

Animals↗
PubMed2001

Diffuse esophageal leiomyomatosis with perirectal involvement mimicking Hirschsprung disease.

We describe a 25-year-old woman with diffuse esophageal leiomyomatosis. During childhood, achalasia was mistakenly diagnosed in this patient. Subsequently, she underwent cardiomyotomy and developed symptoms of Hirschsprung disease. These symptoms were caused by infiltration of the esophageal and rectal walls by benign muscular hypertrophy. The pseudo-Hirschsprung disorder was manifested by chronic severe constipation, with consistent manometric findings. Clitoral hypertrophy and vulvar and periurethral leiomyoma were also present. Genetic analysis demonstrating deletion of the COL4A5/COL4A6 locus and the discovery of microscopic hematuria implied that the patient could transmit both diffuse leiomyomatosis and the Alport syndrome.

Adult↗
PubMed2001

Evidence for further genetic heterogeneity in nephronophthisis.

BACKGROUND: A new type of nephronophthisis (NPH) has been recently identified in a large Venezuelan kindred: adolescent nephronophthisis (NPH3) causes end-stage renal disease (ESRD) at a median age of 19 years. The responsible gene (NPHP3) maps to 3q21-q22. NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, polydipsia, and secondary enuresis. Histopathological findings consist of tubular basement membrane changes, cysts at the corticomedullary junction, and a chronic sclerosing tubulointerstitial nephropathy. The only difference is a younger age at ESRD in NPH1 (median age of 13 years) when compared with NPH3. METHODS: In order to evaluate whether there might be a fourth locus of isolated nephronophthisis, we studied eight NPH families without extrarenal disease manifestations and without linkage to the NPH1 locus (NPHP1) on chromosome 2q12-q13. ESRD was reached at ages ranging from 7 to 33 years. Individuals were haplotyped with microsatellites covering the genetic locus of NPHP3. Infantile NPH (NPH2) was excluded in all families by the clinical history and histological findings. RESULTS: In four of the examined families haplotype analysis was compatible with linkage to the NPHP3 locus. In one of these families identity by descent was observed. In contrast, in another four families linkage was excluded for NPHP3. CONCLUSION: Four NPH-families were neither linked to NPHP1 nor to NPHP3, indicating further genetic heterogeneity within the group of nephronophthisis. The finding of further genetic heterogeneity in NPH has important implications for genetic counselling.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns.

BACKGROUND: Cystinosis is an autosomal recessive disorder characterised by an intralysosomal accumulation of cystine, and affected individuals progress to end-stage renal failure before the age of ten. The causative gene, CTNS, was cloned in 1998 and the encoded protein, cystinosin, was predicted to be a lysosomal membrane protein. RESULTS: We have cloned the murine homologue of CTNS, Ctns, and the encoded amino acid sequence is 92.6% similar to cystinosin. We localised Ctns to mouse chromosome 11 in a region syntenic to human chromosome 17 containing CTNS. Ctns is widely expressed in all tissues tested with the exception of skeletal muscle, in contrast to CTNS. CONCLUSIONS: We have isolated, characterised and localised Ctns, the murine homologue of CTNS underlying cystinosis. Furthermore, our work has brought to light the existence of a differential pattern of expression between the human and murine homologues, providing critical information for the generation of a mouse model for cystinosis.

Journal Article↗
PubMed2000

Glomerular expression of type IV collagen chains in normal and X-linked Alport syndrome kidneys.

Alport syndrome is an inherited nephropathy characterized by alterations of the glomerular basement membrane because of mutations in type IV collagen genes. COL4A5 mutations, causing X-linked Alport syndrome, frequently result in the loss of the alpha5 chains of type IV collagen in basement membranes. This is associated with the absence of the alpha3(IV) and alpha4(IV) chains and increased amounts of alpha1(IV) and alpha2(IV) in glomerular basement membranes. The mechanisms resulting in such a configuration are still controversial and are of fundamental importance for understanding the pathology of the disease and for considering gene therapy. In this article we studied, for the first time, type IV collagen expression in kidneys from X-linked Alport syndrome patients, using in situ hybridization and immunohistochemistry. We show that, independent of the type of mutation and of the level of COL4A5 transcription, both COL4A3 and COL4A4 genes are actively transcribed in podocytes. Moreover, using immunofluorescence amplification, we were able to demonstrate that the alpha3 chain of type IV collagen was present in the podocytes of all patients. Finally, the alpha1(IV) chain, which accumulates within glomerular basement membranes, was found to be synthesized by mesangial/endothelial cells. These results strongly suggest that, contrary to what has been found in dogs affected with X-linked Alport syndrome, there is no transcriptional co-regulation of COL4A3, COL4A4, and COL4A5 genes in humans, and that the absence of alpha3(IV) to alpha5(IV) in glomerular basement membranes in the patients results from events downstream of transcription, RNA processing, and protein synthesis.

Adolescent↗
PubMed2000

[Prenatal diagnosis of autosomal recessive polycystic kidney disease].

OBJECTIVE: Prenatal ultrasonographic detection of autosomal recessive polycystic kidney disease (ARPKD) is of poor reliability, especially in early pregnancy. Molecular genetics allows earlier diagnosis, from 11 weeks of gestation; however, since only indirect diagnosis is possible--the ARPKD gene being localized on chromosome 6 but not identified--the feasibility of molecular diagnosis requires several conditions: definitive diagnosis in the index case, availability of index case and parents' DNA, genetic informativity of the family at the ARPKD locus. Results and limits of this method are analyzed, using a series of 56 requests for prenatal diagnosis. RESULTS: In eight of the 56 families ARPKD was excluded on the basis of histological (seven cases) and/or genetic (two cases) criteria. Molecular study was impossible in three families due to the lack of index case's DNA, and two other families were non-informative. Among the 43 families in which prenatal diagnosis was feasible, analysis of the haplotype of 35 fetuses issued from 29 families showed that 11 fetuses with the same haplotypes as that of the index case were affected, while 24 were not. No false positive or false negative result was reported. CONCLUSIONS: Early and reliable prenatal diagnosis of recessive polycystic kidney disease is possible in nearly 80% of affected families.

DNA↗
PubMed2000

NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.

Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.

Animals↗