Luke's Tuberous Sclerosis Page
Genetic Research Part Two |
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PRODUCTS OF THE VAV2 GENE AND EVIDENCE FORSTRUCTURAL REARRANGEMENTS IN THIS GENE REGION IN TSCl PATIENTS Moyra Smith, K.Handa, WeiHe Dept. of Pediatrics, University of California, Irvine We have analyzed the genomic organization of the Vav2 gene region and have determined that it extends over at least l7Qkb on chromosome 9q34.3.Analysis of cosmids and of human genomic DNA revealed that DNA sequence highly homologous to the Vav2 exon 1 sequence is duplicated and occurs in a position telomeric to the rest of the Vav2 gene. We have also demonstrated that DNA sequence highly homologous to Vav2 exon 2 and exon 3sequence is duplicated in a position centromeric to the known Vav2 gene. These results indicate that in addition to the previously described Vav2 gene, there are additional Vav2 genes or pseudo genes on chromosome 9q34.3. We have analyzed Vav2 transcription products through examination of Northern blots of poly A 'a RNA from different adult and fetal tissues, using three different Vav2 exons as hybridization probes. These results indicate that in all tissues examined, with the exception of lymphoblastoid cells, the majorVav2 transcript is 6kb in size. There are additional Vav2 transcripts 2.4,1.8 and O.6kb in size which show tissue specific and temporal differences in expression. Our analysis of large genomic DNA fragments derived using rare cutting restriction endo nucleases and separated on pulsed field gel electrophoresis indicate the presence of structural rearrangements in the Vav2 gene region in a number of patients with Tuberous sclerosis. The occurrence of multiple copies of Vav2 gene or of specific Vav2 exons and / or Vav2 pseudogenes, could predispose to unequal crossing over during meiosis and thus lead to structural rearrangements which may play a role in the cause on of Tuberous sclerosis. A 1.5 Mb COSMID ANTIGEN COMPASSING THE TSC1 CANDIDATE REGION ON CHROMOSOME 9q34. Joseph Nahmias, Nick Hornigold,Marjon van Slegtenhorst, Janet Young, Steve Jeremiah, Mari-Wvn Burley',Rosemary Ekong, Sophie Rousseaux, Margaret Fox, David Kwiatkowsld', SuePovey and Jonathan Wolfe. The Galton Laboratory, UnIversity College London, Wotfson House. 4, Stephenson Way,London N'Wl 2HE Department of Clinical Genetics, Erasmus University, Dr.Molewaterplein 50 3015 GE Ronerdam Harvard Medical School, Brigham and Women's Hospital, Longwood Medical Research Center, 221Longwood Avenue, Boston, MA 02113 USA The genetic disease Tuberous sclerosis has been shown to be caused by mutations in one of two genes, one of which, TSCl, has been assigned by linkage analysis to 9q34. There is a general consensus that TSCl maps with in the interval D98149 to DYSll4, a genetic distance of 6cM, although contradictory evidence from two recombination events within this interval makes the exact position undefinable. Using a cosmid fingerprinting and contig assembly technique (Nahmias etal 1995) we have constructed a deep cosmid contig (with 2 gaps) spanting this interval. The total length of genome contained within the contigs is approximately 1.4 Mb. In the course of this assembly, in situ hybridisaflon of cosmids from the ends of the contigs to extended chromatim has enabled us to estimate the sizes of gaps between contigs and has led in some cases to the closure of gaps. Published physical mapping data based on interphase FISH measurements and on YAC contig assembly suggest that this genetic interval corresponds to a physical distance of from 2.0 to 2.5Mb.Our estimates of the remaining gaps are smaller than those implied by these figures. We have isolated candidate genes across this region by exon trapping and by positioning ESTs. Nahmias et al 1995 Eur. J. Hum.Genet. 3 65-77 A dense STR map of 1.5 Mb of 9q34: small reduction in the TSCl critical region Kwiatkowskil, DHumphreyl. M van Slegtenhorstl. I Attwood2. IL Hainesiffliw Burley3. N Hornigold3, M Smith5, J Nahmias3, S Faure6 and S Povey& 1Harvard AS, BWH, Boston; 2Dept Clin Genet, Erasmus U, Rotterdam; 3TheGalton Laboratory, UCL, London; 4Mol Neurogenet, Harvard MS, MGH, Boston; 5Dept Pediatrics, UC, Irvine; 6Genethon, Evry. The current critical region for the TSCl gene is D9S149 - D9S114. In concert with efforts to generate a contig of this region (Homigold et al.abstract, this meeting), we have identified 15 STR markers from this 1.5 Mb interval, and used these markers in analysis of both Venezuelan (Venz) and CEPH reference pedigrees o create a dense genetic linkage map of the region. Six of th5,ese markers are new those with sits> 1000); all six have heterozygosity> 0.7. The S149 - S114interval has distance 4.3 cM (male 6.6 cM, female 3.0 cM) in the Venz, and3.8 cM (male 3.6 cM, female 4.0 cM) in th5,e CEPH. Meiotic mapping permits determination of the following order: S149- (S2127, S2126) - S1830 - S1199 - (S1198, ABO, S164) - S1793 -;150 -DBH - S122 - S66 - S114, which is consistent with5, th5,at predicted by contig construction. There are two hot-spots for recombination in this region, the S1199 -;1198 and 31793 -5114 intervals, where th5,e cM/Mb ratios are 6 and 4, respectively. Application of th5,esemarkers to previously described families segregating TSC, has resulted in a small reduction in the TSCl critical region, to th5,e S2127 - S114 interval. Analysis of a 4generation family, with5, lod score of 2.0 with5, 9q34 markers, indicates that an affected individual shows recombination with5, both 3149 and 32127,but not other markers described here. MOLECULAR GENETICS OF TUBEROUS SCLEROSIS (TSC2) GENE Okio Flino, Toshiyuki Kobayashi, Haruo Tsuchiya, Kenji Orimoto, ShinjiUrakami, Toshiki Yamamoto, Kazunori Kajino, Yasushi Kikuchi and RideakiYasui. Department of Experimental Pathology, Cancer Institute, 1-37-1Kami-Ikebukurn, Toshima-Icti, Tokyo 170, Japan The Eker rat hereditary renal carcinoma (RC) is an excellent example of amendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a gerniline insertion in the rathomologue of the human tuberous sclerosis (TSC2) gene gives rise to the dominantly inherited cancer in the Eker rat model (NatureGenetics, 9: 70-74, 1995) and a tumor suppressor nature for Tsc2 gene function (Proc. Natl. Acad. Sci. USA, 90: 327-331 1993., Cancer Res., 34:2633-2633, 1994., Cancer Res., 55: 939-99%, 1995., Biochem. Biophys. Res. Commun., 219: 70-73, 1996). Investigation of extra-renal primary tumors co-occurring in Eker rats late in life (at 2years) additionally revealed enhanced development of probable hemangio sarcomas of the spleen, uterineleiomyo sarcomas, and pituitary adenomas, although the demonstrated prediction for these extra-renal flirnors was not as complete as with RCs (Cancer Lett. 83:117-121, 1994. Transplantasion Proceedings 27:1329-1331,1995). We further detected LOM in all but the splenic tumors, suggesting that inactivation of the Tsc2 gene is also a critical event in the pathogenesis of these extra-renal lesions(Jpn. J. Cancer Res. 86: 828-832, 1993). Microsatellite instability was not observed in Eker rat tumors (Molecular Carcinogenesis, 14: 23-27, 1995). The phenotype of tuberous sclerosis in humans differs from that in the Ekerrat, except for the occurrence of RCs (in humans, angiomyolipomas are more common). We determined the entire cDNA including several alternative splicing variants and the exon-intron organization of the rat Tsc2 gene (Nucleic Acids Res., 23: 2608-2613,1995). The rat Tsc2 product shows a 92% amino acid identity to the humane counterpart. Surprisingly, the rat Tsc2 gene consists of 41 exons, although there is non-coding exon in the 5' upstream region (submitted). We have already found intragenic mutations in the Tsc2 gene by PCR-SSCP analysis(submitted) and transcriptional activation domains in the C-terminus of theTsc2 product. while a C-terminal truncated Tsc2 protein was localized in the nucleus, the fill length protein is predominantly found in the perinuclear region of cytoplasm(Cancer Res. 56: 429-433, 1996). It is well-known that TSC shows a variety of phenotypes even within the same family. Since nothing is known about the molecular mechanism in human tuberous sclerosis, the Eker rat has special potential value for studying TSC2 gene function, species-specific differences, and their role in tumor igenesis, eventually leading to treatment of patients. THE TUBEROUS SCLEROSIS GENETC2 IS A TUMOR SUPPRESSOR GENE WHOSE PROTEIN PRODUCTCO-LOCALIZES WITH ITS TARGET RAP1 IN TEE GOLGI STACKS. Raif Wieneoke' John C.MMze Jr.1. Douglas R. Lowy1,Fang fin2. Fariha Shoarinejad2. Raymond S. Yeung2. Jean de Gunzburg3. and JeffrevE. DeClue1. 1National Canoer ffistimte, Bechesda. NID. USA; 2Division oil Nledioal Science, Fox Chase Canoer Center, Philadelphia. PA,USA; 3geocion de Reoherohe. Thscicuc Curie. Paris.Franoe. W are exploring the hypothesis that TSC2, which is mutated in some tuberous sclerosis (TSC) families, is a tumor suppressor gene whose protein product tuberin mediates its activity through the inceraccion with the Ras-related protein Rap 1. Our laboratory has previously identified the1 8O-kDa tuberin protein in cell lysates and shown that tuberin exhibits a weak but specific GTP are activating activity in vitro towards Rap 1, Suggesting that tuberin may function as a negative regulator for Rap 1. We have now examined the tissue distribution arid suboellular localization of tuberin, tested the potential growth inhibitory activity ofTSC2. arid screened sporadic tumors for tuberin expression. Our tissue analysis has found that tuberin is widely expressed; consistent with the phenotype of TSC, the highest levels of tuberin are detected in adult human brain, heart and kidneys. Immuno histo chemical analysis of sections of normal human tissues with affinity purified anti-tuberin antibodies revealed a distinct staining pattern in certain cells, including the arterioles of the kidney, skin, arid heart, arid the pyramidal neurons arid Purkinje cells%f the brain arid cerebellum. In many of these cells, abundant staining was also observed when affinity .purified anti-Rap I aritibodies were employed. To examine the subcellular localization of tuberin in greater detail, double-indirect immuno fluorescence analysis was carried out with cultured cell lines, using affinity-purified anti-tuberin antibodies in conjunction witharitibodies against proteins which are specifically expressed in the Golgi apparatus. The results demonstrated that most of the tuberin is localized to the Golgi stacks. In addition, brefeldin A, a drug known to destroy the Golgi, abolished anti-tuberin immuno fluorescence. Consistent with the hypothesized physiologic interaction between tuberin arid Rap 1 in vivo, double-indirect immuno fluorescence arid corifocal trucroscopy monstrated co-localization of the two proteins in cultured cell lines. To experimentally evaluate a possible tumor Suppressor fianction of TSC2,the in vivo Sects of tuberin Overexpression were studied in two different cell systems. Regulated pression of full-length TSC2under the control of a tetracycline-responsive promoter in tI fibroblasts expressing the tetracycline-repressorjvpl6 trans activator protein resulted in 2 - 5 fold overexpression of tuberin upon the removal of tetracycline. In these cells, the induction of tuberin sigularity inhibited cell growth. Consistent with a tumor Suppressor function, expression of full-lengthTSC2, or a sub-clone encoding the C-terminal 760 amino acids of tuberin into the tuberin negative, Eker rat-derived, ERC 1 8M arid LexF2 cell linesSuppressed anchorage-independent growth arid tumorigenicity. We also obtained evidence that TSC2 may function as a tumor suppressor gene in sporadic human tumors, as several brain tumors from non-TSC patients were found to lack detectable tuberin expression. The direct growth-suppressive effects of TSC2 and the loss of tuberin in tumors tepresent experimental evidence that TSC2 is a tumor suppressor gene. The co-localization Of tuberin arid Rap 1 in vivo strengthens the likelihood that the in vitro catalytic activity of tuberin upon Rap 1 is physiologically relevant. These findings suggest a mechanism of tuberin function that may help explain some of the clinical manifestations of TSC. SSCP ANALYSIS OF THE GAP RELATED DOMAIN OF THE TSC2 GENE. M Maheshwar. J.P Cheadle. A. Jones. J.Myring. 'A.E. Fryer.and J.R. Sampson. Institute of Medical Genetics, University of Wales of College ofMedicine, Cardiff, UK. 'Mersey Regional Genetics Service, Liverpool,UK. Tuberous sclerosis (TSC) is an autosomal dominant, multi system disorder, characterized by seizures, mental retardation and a variety of hamartomatous lesions in many tissues and organs. Linkage studies demonstrate that approximately 50% of TSC families segregate with an unidentified gene which maps to chromosome 9 (TSC 1), while the remainder are associated with a gene which maps to 16p13.3 (TSC2). Loss of heterozygosity across the TSCl and TSC2 chromosomal regions in TSC associated hamartomas suggests that both genes act as tumour Suppressor genes serving related functions. Tuberin, the human TSC2 gene product, has a region of homology with rap 1 GAP and stimulates rap 1 GTPase activity in vitro, Suggesting that one of its cellular roles is to function as a GTPase activating protein (GAP). Homology between tuberin and raplGAP spans exons35-39 of the TSC2 gene, and this region is highly conserved in human and Fugri rubripes, supporting the functional importance of this domain. We have undertaken mutational analysis of exons 35 - 39 of the TSC2 gene in 163 unrelated TSC patients by SSCP analysis of genomic DNA. Direct Sequencing of all aberrant bands and analysis of samples from appropriate family members has been undertaken to characterize all putative mutations. To date, 3 deletions, 8 missense mutations, 2 nonsense mutations, 2 splice site mutations and 7 polymorphisms have been characterized. A further 3 putative mutations are undercharacterisation. These results help confirm the GAP related domain as a functionally important region of tuberin. TSC2 MUTATION DETECTION AND TUBEROUS SCLEROSIS LOCUS ASSIGNMENT BY SOUTHERNBLOT, LOSS OF HETERZYGOSITY ANALYSIS AND PROTEIN TRUNCATION TEST. L. Longa, A. Brusco, S. Polidoro, B.Grosso, C. Carbonara, N. Migone CNR-CIOS and Dipartirnento di Genetica,Biologia e Chimica Medica, Universith di Torino, Italy. 135 families with one or more members affected by tuberous sclerosis have been reported at our center for the molecular analysis of the gene defect. Clinical examination of the proband relatives identified39 faminial cases. Linkage analysis was performed in 14 cases, the 25remaining families being not feasible for linkage analysis due to the small number of affected relatives or the limited clinical data available. TSCl or TSC2mikage was observed in 5 and 2 families respectively. In the 7 remaining families both loci were compatible with the haplotypes segregation. 97unrelated pro band not clearly linked to TSCl, were studied by means of Southern blot of BcoRI+HindIII digested DNA and a full lengthTSC2 cDNA probe. Two large TSC2 and PKDl gene deletions (>175 kb), and three TSC2partial deletions (1, 11 and 40 kb) were documented, in addition to twoHindIll polymorphisms (in intron 11 and in exon 37, respectively) of no clinical significance. As previously reported, in 8 of 19 patients (40%)the loss of heterozygosity analysis on pathologic tissue specimens identified the affected locus. We are presently using the Protein Truncation Test (PIT) as the first screening approach. Seven overlapping rPCR segments of 800-1.100 bp representing the full length TSC2 niRNA were transcribed and translated in vitro. So far, 10 patients were fully tested by PT,T and9 patients were partially tested (more than 60% of the TSC2 sequence): 6 were TSC2-liniced and 13 unassigned to either locus. Eleven (4 from theTSC2-linked and 7 from the unassigned group) showed truncated proteins. We will present our preliminary data on sequence analysis of the mutations and on the detection rate of PIT test in a larger set of patients. This work was partly supported by Telethon (grant no. E.143) and by"Associazione E. & E. Rulfo per la Genetica Medica". MUTATION DETECTION OF THE TUBEROUS SCLEROSIS TSC2 GENE USING SSCP AND CHEMICAL MISMATCH CLEAVAGE A.Astrinidis1, A.Kouvatsi1,J.Nalunias2, S.Povey2, C.Pandeliadis3, A.Danz:iki3, M. Schneide?, D.Weinstat-Saslow4, C.Triantaphyflidis1 1 Department of Genetics, Development andMolectilar Biology, School of Biology, Aristotle University ofThessaloniki, 54006 Thessaloniki, Greece 2 Human Biochemical Genetics Unit, Medical Research Council, The Galton Laboratory, Wolfson House, University CoUege London, 4 Stephenson Way,NW 1 2HE London, UK 3 Third Paediatric Clinic,Hippoluntion Hospital of Thessaloniki, 54642 Thessaloniki, Greece 4 Brigham and Womens Hospital, School of Medicine, Harvard University, Renal Division MRB318, Boston, MA 02115, USA Mutations in the TSC2 gene on chromosome l6pl3.3 have been estimated to be responsible for approximately half of the familial cases of Tuberous Sclerosis. Large rearrangements or deletions of the TSC2 gene have previously been reported in a small number of patients(Brook-Carter et at 1994, Carbonara et at 1996) and recently a number of point mutations have been identified and have been thought to have caused the disease (Kumar et at 1995,Vrtel et at 1996, Wilson et at 1996). We have employed the techniques of SSCP and chemical cleavage to search for mutations in patients from the UK and from Greece. DNA samples from 23unrelated patients with unequivocal signs of Tuberous sclerosis were studied Of these 9 were from families in which segregation for TSC2 had been demonstrated by linkage analysis, 7 were from families in which the linkage information was inconclusive and 7 were sporadic cases. In the sporadic cases both parents had always been clinically assessed but DNA was not available from both parents in every case. Samples were amplified by PCR, producing fragments varying in size from 220bp to 1200bp and subjected to SSCP analysis and Chemical Mismatch Cleavage (CMC). Nine out of 41 exons were partially screened using either SSCP or CMC analysis and in some instances both the techniques. Four persons(two Greeks and two British) showed CMC fragments of different size. In all cases the results were also observed in other members of the patients' families but in only one family the altered fragments segregated together with the inheritance of the disease. The PCR products were sequenced and the responsible DNA changes were localised in the intron between exons 4 and 5. In one case it is possible that the nucleotide change detected has altered the splicing of the QiRNA but it seems more probable that these changes reflect polymorphisms. This is being investigated by screening as et of unrelated healthy individuals, using CMC. Investigation impossible mutations in other areas of the TSC2 gene is in progress. Acknowledgements We would like to thank Dr. Julian Sampson and Dr. Magitha Maheshwar (Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, LX) for kindly providingsequence of the TSC2 genomic region. We would like to thank the Tuberous Sclerosis Association-U.K. and the British Council-Greece for supporting J.N. and A.A. respectively. This project was partially financed from the Greek Ministryof Development (programme PENED 1995). References Carbonara C. etat (1996) Genes Chromosomes and CancerVol.15, No.1, pp.18-25 Kumar A. etat (1995) Hum. Mol.Genet. Vol.4, No.12,pp.2295-2298 Brook-Carter PT.etat (1994) Nat.Genet. Vol.8, pp. 328-332 Vrtel R. etat (1996)J. Med. Genet. Vol.33, No.1, pp.47-51 Wilson P.J. et at (1996) Hum. Mol. Genet. Vol. 5, Nr. 2,pp.249-256 PHYSICAL AND GENETIC ANALYSIS OF TWO NEW INSERTION/DELETION POLYMORPHISMS IN INTRONS 2 AND 8 OF TCS2 S. Padovan, C. Carbonara, L.Longa, S. Polidoro, N. Migone. CNR-CIOS and DiPartimento di Genetica,Biologia e Chitnica Medica, Universith di Torino, Italy. The KG8 micro satellite is at present the most informative and closest "marker to the TSC2gene for family segregation and loss of heterozygosity analysis. The heterozygosity of KG8 is however not very high (64% observed in our panel of 86 subjects). Here we present two new polymorphisms due to insertion/deletion of repetitive sequences in int:rons 2 and 8 of TSC2. The first polymorphism in intron 2 consists in an insertion of a 332 bp that contains an Musequence and a I 6-bp direct repeat The insertion occurred within a 200 bp segment flanked by two other nonpolymorphic Mu repeats. Indeed, intron 2 appears particularly rich in Mu, since two additional Murepeats were found by sequencing approximately two-thirds of IVS2. This polymorphism is testable by PCR: 454-bp and 236-bp fragments correspond to WS2-Al and IVS2-A2, respectively.IVS2-Al and -A2 frequencies counted in 174 chromosomes are 0.15 and 0.85;the observed heterozygosity is 26%. The second polymorphism is due to a variable number of 29-bp repetitive units present in intron 8. Mso this polymorphism can be tested by PCR: three allelic fragments of 570 (IVS8-A1), 540 (rVS8-A2) and 510 bp(IvS8-A3) were found in 175 chromosomes. The IVS8-A1, -A2 and -A3 gene frequencies are 0.051, 0.777 and 0.172, respectively. The observed heterozygosity is 36%. As expected, the IVS2, IVS8 andKG8 alleles are in linkage disequilibrium. However, 10 of the 31individuals non informative for KG8 appeared heterozygous at the WS8 locus, and 4 of these 10 were heterozygous atIVS2 as well. In conclusion, these two novel intragertic markers might be helpful in the PCR screening for TSC2 deletions, loss of heterozygosity analysis, and in about 30% of KG8-noninformativeindividuals. This work was party supported by Telethon (grant no. E.143) and by"Associazione E. & E. Rulfo per la Genetica Medica". TUBEROUS SCLEROSIS ASSOCIATED WITH HYPOMELANOSIS OF ITO. A CONTIGUOUS GENE SYNDROME? P.Balestri, G.Bartalini, C.DiLucca and A.Fois. Pediatric Institute, University of Siena, Italy. D.J.J. Halley, J.O.Van Hemel, B.Eussen and A.M.W.van den Ouweland.Department of Clinical Genetics, Erasmus University, Rotterdam, TheNetherlands We have recently observed an 11 year old by (propositus) in whom a diagnosis of Tuberous Sclerosis Complex (TSC) had been made on the basis of the presence of facial angiofiibrnmas, fibrous forehead plaque, 3hypopigmented skin spots, complex partial seizures, mental retardation, cerebral cortical tubers and subependymalnodules on MR'. His brother, from the father's first marriage, also had TSC. He died at 18 years of age after intraperitoncal haemorrhage due to renal angiomyolipoma. However the father showed no signs of TSC at the clinical and instrumental examination including fundoscopy, renal and cardiac ultrasound, and brain MRI. This situation can be explained by ageumline mosaicism. Besides the signs indicating the diagnosis of TSC, the propositus showed additional dysmorphic facial features consistent with a triangular face, high forehead, hypertelorism, epicanthal folds, broad nasal rcot, narrow and high arched palate, hypertrophic alveolar ridges and microcephaly. Furthermore he had a well demarcated1.5 cm wide hypopigmented streak which started from the left groin and proceeded linearly to the malleolus. Another irregular hypopigmented area was present on the left lower abdominal region. On the basis of these latter findings, a diagnosis of Hypomelanosis of Ito (HI) concomitant with TSC has been considered. The child also had another interesting haematologic finding: his bloodsmear showed microcytic red blood cells with MCV = 66fl without an elevated level of Hb A2; the possibility of an aIpha-Thalassemia trait has been considered and molecular investigations are now in progress. TSC shows genetic heterogeneity with one gene, TSCl, mapped to chromosome 9q34 and a second ,TSC2, to l6p13.3. A wide variety of chromosome abnormallties mostly in themosaic form have been found in Hypomelanosis of Ito but there is no cleargene assignment yet. Mpha globin gene cluster is located in the16pl3.3-pter segment near the TSC2 gene. Individuals with alpha-Thalassemialmental retardation syndrome due to a constitutional terminal l6p deletion positioned distally to the TSC2 locus have been described. In our patient FISH analysis with the cosmid probes CCI-2, CBFSl, CW9D and CW23(5) was applied on lymphocyte metaphase spreads. This analysis resulted in one signalon the chromosome 16, indicating a molecular deletion in the TSC2 gene. These data suggest that the clinical features of our patient can be related to a large deletion spanning contiguous genes and that there is strong evidence that at least one HI locus can be assigned to this region. Therefore HI can be considered part of this contiguous gene syndrome. DNA studies, now in progress to determine the extent of the deletion outside the TSC2 gene, will give further information about this possibility. A TUBEROUS SCLEROSIS PATIENT WITH A LARGE TSC2 AND PKD1 GENE DELETION SHOWS EXTRA-RENAL SIGNS OF POLYCYSTIC KIDNEY DISEASE(Plo 1) L. Longa', A. Brusco', C.Carbonara', S. Poljdoro', F. Scolari2, B.Vaizodo2, P. Riegler3, N. Migone'. ' CNR-CIOS and Dipartimento di Genetica, 3Biologia e Chimica Medica, Universith diTorino; 2Servizio di Nefrologia, Spedali Civili, Brescia;Servizio di Nefrologia, Ospedale Generale Regionale, Bolzano, Italy. The renal lesions in tuberous sclerosis are multiple angiomyolipomas often associated with cysts of variable size. Symptoms or signs of renal failure are uncommon before the age of 30 years. A few TSC patients with an early-onset renal failure and renal cysts resembling the adult polycystic kidney disease have recently been described. All of them are sporadic and show deletions of variable portions of both TSC2 and PKDl genes. We have observed a two-generation family in which TSC and Ploco-segregate with a TSC2 and PKDl gene deletion. The proband, a 30-year-old man, was diagnosed carrying both TSC and PKD at 12 yr. of age. He developed chronic renal failure requiring bemodialysis at 28 yr. Interestingly, abdomen CT scan and cerebral angiography revealed in addition to enlarged polycystic kidneys, multiple liver cysts and a snat cerebralaneurysm, i.e. typical extra-renal signs of the adult PKD phenotype. His mother had facial angiofibromas. Plo was diagnosed at 34 yr. Eight years later, she begun hatmodialysis and at 44 was nephrectomized for urinary sepsis. Bilateral angiomyolipomas and enlarged cysts were found in her kidneys. She died 3yr. later of breast cancer. In the proband, Southern blot, PFGB, and16p13.3-linked microsatellites analysis showed a 175-kb deletion on the maternal haplotype, spanning the entireTSC2 and the large majority of Plol exons. The segregation of 16p13.3-linkedrnarkers in the mother and in seven healthy sibs of her, confirmed that she too carried the deletion. These findings suggest that the full APlo phenotype may develop starting from agenline, Piol mutation, likely belonging to the loss-of-function type. Finally, this is the first report of familial occurrence of the PIW and TSC contignous gene syndrome. In a second unrelated TSC patient who manifested the end-stage renal failure at 19 yr. and polycystic kidney we found a large gurinine, de novo deletion, spanning the entire TSC2 and Plo 1 genes and loss of heterozygosity at multiple TSC2 and Plol markers within' an angiomyolipoma from the explanted kidney. Bxt etra-renaisigns of Plo in the latter patient are presently under careful investigations. This work was partly supported by Telethon (grant no. E.143) and by"Associazione E. & E. Rulfo per la Genedca Medica". This home page is intended to be a family resource for families affected by Tuberous Sclerosis. It does not intend to constitute medical advise. Viewers are warned not to take any action with regard to medical treatment relying on the information provided on this page without first consulting the patient's physician.
Deanna Runyan-Wall E-mail address: deannadawn@lukets.org Last updated: April 5, 2008 Created: December 5, 1996 |
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