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Molecular mechanism for duplication 17p11.2 - the homologous recombination reciprocal of the Smith-Magenis microdeletion.
Author: Potocki, L., et. al.
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"letter 84 nature genetics ? volume 24 ? january 2000 Molecular mechanism for duplication 17p11.2? the homologous recombination reciprocal of the Smith-Magenis microdeletion Lorraine Potocki 1,2 *, Ken-Shiung Chen 1 *, Sung-Sup Park 1 , Doreen E. Osterholm 1 , Marjorie A. Withers 1 , Virginia Kimonis 3 , Anne M. Summers 4 , Wendy S. Meschino 4 , Kwame Anyane-Yeboa 5 , Catherine D. Kashork 1 , Lisa G. Shaffer 1 & James R. Lupski 1,2 *These authors contributed equally to this work. 1 Department of Molecular and Human Genetics, 2 Department of Pediatrics and Texas Children?s Hospital, Baylor College of Medicine, Houston, Texas, USA. 3 Department of Pediatrics, Southern Illinois University, School of Medicine, Springfield, Illinois, USA. 4 Department of Genetics, North York General Hospital, Toronto, Canada. 5 Department of Pediatrics, Columbia University, New York, New York, USA. Correspondence should be addressed to J.R.L. (e-mail: jlupski@bcm.tmc.edu). Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrange- ments associated with many genetic disorders 1 . Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A; ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A?REPs, results in a 1.5-Mb dele- tion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syn- drome (SMS) is a multiple congenital anomalies, mental retarda- tion syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (refs 3,4). Most patients (>90%) carry dele- tions of the same genetic markers and define a common dele- tion 5?7 . We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junc- tion fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further mole- cular analyses suggest that the de novo 17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical pheno- type resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homolo- gous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined. We have shown previously that recombination between flanking repeat gene clusters (SMS?REPs) leads to the SMS deletion by identifying a novel junction fragment of the same apparent size in multiple patients 8 . Several independent studies have also iden- tified repeat gene clusters flanking common microdeletion breakpoints in Williams 9?11 , Prader-Willi/Angelman 12,13 (PWS/AS) and DiGeorge/velocardiofacial 14,15 (DGS/VCFS) syn- dromes. It is probable that the flanking repeat gene clusters observed in these microdeletion syndromes predispose to homologous recombination events, making those regions sus- ceptible to chromosome deletion, as is the case for SMS. We investigated the hypothesis that homologous recombination and unequal crossing over between SMS?REPs causes duplication of 17p11.2 as the reciprocal event of the SMS deletion. Fig. 1 Two-colour FISH analysis using PMP22, FLII and ZNF179 probes. The PMP22-containing probe was detected with anti-digoxigenin con- jugated to rhodamine (red), the FLII cosmids were labelled with biotin and detected with avidin conjugated to fluorescein isothiocyanate (green). The interphase nuclei were counter- stained with DAPI (blue). a, Idiogram of chromo- some 17p with location of FISH probes. Left, normal chromosome 17. Right, duplication of 17p11.2, the region containing FLII. FISH results from lymphoblast cell lines of patients 990 (b) and 1192 (c) are shown. The normal chromo- some 17 (nl) displayed one red and one green signal, and the abnormal chromosome (dup) dis- played one red signal and two green signals, indicating a duplication of the FLII locus. d, Ideogram of chromosome 17p. Left, 17p with the FLII and ZNF179 locations indicated within 17p11.2. Right, three diagrams of hypothetical orientations for duplication including FLII and ZNF179 loci. A direct duplication of 17p11.2 revealed a distinct pattern by FISH. FISH results from patients 1251 (e) and 1192 (f) are also shown. The ZNF179 locus was detected with anti-digoxigenin conjugated to rhodamine (red), whereas FLII was detected as above. The normal chromosome 17 (nl) displayed one red and one green signal, whereas the abnormal direct dup(17)(p11.2p11.2) chromosome (dir dup) showed a red-green-red-green signal pattern. Patient 1006 (not shown) was previously reported to have a tandem duplication of 17p11.2 on one chromosome 17, and a deletion of PMP22 on the homologous chromosome 27 . a b c d e f � 2000 Nature America Inc. ? http://genetics.nature.com � 2000 Nature America Inc. ? http://g enetics.nature .com letter nature genetics ? volume 24 ? january 2000 85 Chromosome analysis revealed an apparently increased band size for the 17p11.2 region in seven patients ascertained for developmental delay. We performed FISH analysis with proximal 17p probes. The myelin gene PMP22 maps within the 1.5-Mb region in 17p12 that is typically duplicated in CMT1A (ref. 16). FLII, the human orthologue of Drosophila melanogaster flightless- I (fliI), maps to the SMS region in 17p11.2 and is deleted in all patients with SMS (refs 17,18). FISH studies indicated duplica- tion of the SMS region, but not the CMT1A region, in all seven patients (Fig. 1a?c, and data not shown). We used two probes specific for the SMS common deletion region, FLII and ZNF179 (ref. 19), to distinguish direct versus inverted duplications (Fig. 1d). Unequal crossing-over of nonallelic, directly repeated sequences between sister chromatids or between two homologous chromosomes is predicted to generate tandem duplication. FISH results showed direct (tandem) duplications in all seven patients tested (Fig. 1e,f, and data not shown). These results are consistent with the predicted outcome of unequal crossing over between direct repeats, causing a tan- dem duplication of 17p11.2, and inconsistent with an inverted duplication. We used PFGE analyses with an SMS?REP probe to identify a rearrangement-specific junction fragment. SMS?REP is a region-specific, low-copy repeat gene cluster that contains at least four genes, CLPSMCR (for coactosin-like protein from the Smith-Magenis critical region), TRESMCR, KERSMCR and SRPSMCR, and appears to span more than 200 kb (ref. 8). South- ern analyses of NotI-digested genomic DNA from the seven 17p11.2 duplication patients and their parents, using the same CLPSMCR probe that revealed an SMS deletion junction frag- ment 8 , identified an approximately 1.1-Mb de novo junction frag- ment in all patients (Fig. 2a, and data not shown). PFGE analysis using a somatic cell hybrid cell line retaining the duplication chro- mosome detected the de novo junction fragment (data not shown). The junction fragment appears to be identical in size in all patients, within the limits of resolution of PFGE analysis (Fig. 2b). Two patients with cytogenetic duplications involving 17p12, who were also shown to be duplicated for the PMP22 probe using FISH (ref. 20), did not show evidence for a duplication-specific junction fragment using the CLPSMCR probe (data not shown), indicating that DNA recombined in these larger duplications is distinct from that for dup(17)(p11.2p11.2). We determined the parental origins and the mechanism for duplication of 17p11.2 by microsatellite marker analysis (Fig. 3). Among the seven duplication patients, six families were informa- Fig. 2 PFGE detection of novel 17p11.2 duplication junction fragments. PFGE analysis detected the 17p11.2 duplication junction fragment in seven unre- lated 17p11.2 duplication patients. The Southern blot was hybridized with a CLPSMCR cDNA probe, which identified an ?1.1-Mb junction fragment (arrow, jct) present in duplication patients. a, The de novo junction fragment in one family. b, A similar size junction fragment in all duplication patients examined. Saccharomyces cerevisiae chromosomes were used for size markers. Pulsed field data on 990 and 1006 were previously reported 8,27 . Fig. 3 Haplotypes of seven duplication patients and their par- ents. The markers within the SMS common deletion region and their genotypes are shaded. Seven unrelated families (HOU 128, HOU 360, HOU 365, HOU 449, HOU 482, HOU 527 and HOU 532) are shown. The duplication in patient 504 is likely to be derived from paternal interchromosomal recombination because, for the informative locus (marker D17S2206), the mother contributes only one allele to her child. Patients 990 and 1192 inherited two distinct paternal alleles and one mater- nal allele, thus the duplications in these patients are generated by interchromosomal rearrangement between the two pater- nal homologues. The haplotype generated by unequal crossing over of paternal chromosomes is outlined in bold in patient 990. Haplotype analysis of the unaffected brother (1462) of patient 990 in family HOU 360 enables one to determine the phase of the alleles on the paternal chromosome. The paternal haplotype not subjected to unequal crossing over was inher- ited by the brother of 990, 1462, and is demarcated with dashed lines. Patients 1006 and 1251 reveal a double dosage for the markers inherited from one of the paternally derived chromosomes, suggesting that the duplication in these patients are generated by paternal intrachromosomal rearrangements. A minus sign in patient 1006 and her mother indicates a deletion determined by dosage of the alleles (as previously demonstrated by FISH analysis 27 ). The duplication in patient 1353 is generated by maternal interchromosomal rearrangement. The origin of duplication in patient 1364 can not be determined. a b � 2000 Nature America Inc. ? http://genetics.nature.com � 2000 Nature America Inc. ? http://g enetics.nature .com letter 86 nature genetics ? volume 24 ? january 2000 tive. Of these, five showed that the rearranged chromosome was of paternal origin. For two cases the duplication arose through an intrachromosomal event. In four of six cases, the recombination resulting in the duplication occurred between homologous chro- mosomes (interchromosomal). In one duplication patient (1353), the duplication was derived from a maternal interchro- mosomal recombination, as markers from each maternal homo- logue were represented within the duplicated region in this patient. The haplotype data demonstrated unequal crossing over between homologous chromosomes associated with the duplica- tion in family HOU 360. This fully informative family had an unaffected sibling, which allowed for phasing of the alleles. The same markers duplicated in these patients were contained within the common SMS deletion, suggesting involvement of the same genomic region in both rearrangements (data not shown). The clinical findings in the seven patients studied with dup(17)(p11.2p11.2) are shown (Table 1). The phenotype is rela- tively mild with generally normal appearing facies (except in patients 504 (ref. 21) and 1251), mild to borderline men- tal retardation and behavioural difficulties. A proportion of patients have short stature (5/7; height below the fifth percentile for age) and dental abnormalities (6/7) such as malocclusion and crowded teeth. No major organ devel- opmental abnormalities were seen in these patients, in contrast with patients deleted for this region 2 . Our results on seven patients with de novo dup(17)(p11.2p11.2) show a novel junction fragment that is specific to these patients and to their rearranged chromosomes, and of similar size within the limits of resolution of PFGE. The same probe that revealed an SMS deletion-specific junction fragment detected the junction fragment in the duplication patients. Unequal crossing over of flanking markers was demonstrated by haplotype reconstruction. The genetic markers dupli- cated in these patients are the same as those deleted in SMS patients with the common deletion. Our data are consistent with the hypothesis that homologous recom- bination and unequal crossing over between SMS?REPs cause the 17p11.2 duplication and the SMS deletion as reciprocal recombination products (Fig. 4). Supportive of the predicted outcome of the unequal crossing-over event, the hybridization pattern of two-colour FISH using two gene probes derived from within the SMS common deletion region exhibited a pattern implying a direct duplication. Our data also suggest that de novo dup(17)(p11.2p11.2) may preferentially occur during paternal gametogenesis, although additional duplica- tion patients must be analysed before a firm conclusion can be derived. In contrast with the findings in CMT1A, Table 1 ? Clinical findings of duplication 17p11.2 Short Mental Behavioural Dental Other Patient Age Gender stature retardation a abnormalities abnormalities Seizures findings 504 b 6 y 6 m M yes borderline hyperactive yes no hypotonia, poor balance (74) dysmorphic features c 990 9 y 10 m M no mild autistic d yes by EEG submucous cleft palate (65) bifid uvula 11 y 3 m variable e non-autistic d 1006 b 14 y F yes mild attention deficit yes no growth hormone (62) deficiency 1192 10 y 6 m F yes mild attention deficit yes febrile x1 oral apraxia (65) microcephaly 1251 3 y 2 m F no low average no no yes dysmorphic (83) features f 1353 17 y M yes mild hyperactive yes no hypotonia (early) obsessive/compulsive 1364 41 y M yes mild hyperactive yes no obesity as adult post puberty notably good balance a Full-scale IQ results are given in parentheses. b Patients 504 and 1006 are reported in refs 20, 21 and 27, respectively. c Triangular face, downslanting palpebral fissures, mandibular and maxilary hypoplasia, smooth philtrum, high arched palate with thick palatine ridges, posteriorly angulated and prominent ears. d Childhood autism rating scale: age 9 y 10 m, ?autistic?; age 11 y 3 m, ?non-autistic?. e Results varied from the moderate range (55) on the Wechsler Math Composite, to the low average range (84) on the Wechsler reading composite, to the normal range (102) on the test of non-verbal intelligence (TONI-2). f Triangular face, mild frontal bossing, beaked nose, smooth philtrum and high arched narrow palate. Fig. 4 Genomic rearrangements of 17p11.2 resulting from recombination between proxi- mal (SMS?REPP, rightward grey cross hatch) and distal (SMS-REPD, leftward black cross- hatch) repeat gene clusters. The SMS?REPs, PMP22 (open oval), FLII (black oval) and ZNF179 (grey oval) are represented on each homologous chromosome. SMS?REPM (ref. 8) is omit- ted from the figure for simplicity. Capital letters (A?D and A�?D�) refer to the flanking unique sequences on the homologues; A on the centromeric side and D on the telomeric side. The proximal and distal SMS?REPs can misalign during meiosis as illustrated. An unequal crossing-over event occurs between misaligned SMS?REPs via homologous recom- bination. There are two predicted reciprocal recombination products: (i) the SMS deletion (solid arrow); and (ii) the duplication of 17p11.2 (dashed arrow). Each has a unique junc- tion fragment (jct) by PFGE. FLII � 2000 Nature America Inc. ? http://genetics.nature.com � 2000 Nature America Inc. ? http://g enetics.nature .com letter nature genetics ? volume 24 ? january 2000 87 in which the paternal rearrangements were exclusively interchro- mosomal and the maternal rearrangements were exclusively intra- chromosomal 22 , we report two paternal intrachromosomal duplications and one maternal interchromosomal rearrangement. We have defined a clinical syndrome based on a shared molec- ular structure among patients. This represents a paradigm shift in medical genetics in that common clinical findings of patients are usually the impetus for delineation of a syndrome and subse- quent discovery of its molecular basis. Duplication of segments of the human genome may eventually be shown to be responsible for many human traits. The human genome project will delineate genome architectural features, such as low-copy, region-specific repeats, which may enable prediction of regions susceptible to rearrangements associated with genomic disorders. Recent reports have postulated that specific genetic loci with flanking repeated gene clusters are associated with other recurrent microdeletions 9?15,23,24 . It remains a distinct possibility that most interstitial chromosomal microdeletion syndromes have corre- sponding microduplication syndromes that represent the recip- rocal recombination product. Methods FISH analysis. We performed two-colour FISH as described 25 on inter- phase nuclei of lymphoblast cell lines derived from the patients. Probes for the PMP22 locus in the CMT1A region 20 , for FLII in the SMS region 17 and the ZNF179 locus in 17p11.2 (ref. 19) were used as reported. PFGE analysis. High molecular weight DNA was isolated in agarose plugs from peripheral blood samples, somatic cell hybrid cell lines and Epstein- Barr virus-transformed lymphoblastoid cell lines established from controls and patients 26 . For Southern analysis, we used the 1.1-kb HindIII fragment from the cDNA clone 41G7A, which contains the 3� end of the coding region and part of the 3� UTR, as the CLPSMCR probe. Marker genotypes. We determined parental origin and chromosomal mechanism of the duplication by microsatellite analysis. Oligonucleotide primer sequences were obtained from the Genome Database (http://www.gdb.org), and the 5� end of forward primers were specifically end-labelled with fluorescent dyes of 6-FAM, TET or HEX (Applied Biosys- 1. Lupski, J.R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417?422 (1998). 2. Lupski, J.R. Charcot-Marie-Tooth disease: lessons in genetic mechanisms. Mol. Med. 4, 3?11 (1998). 3. Chen, K.-S., Potocki, L. & Lupski, J.R. The Smith-Magenis syndrome [del(17)p11.2]: clinical review and molecular advances. Ment. Retard. Dev. Disabil. Res. Rev. 2, 122?129 (1996). 4. Greenberg, F. et al. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am. J. Med. Genet. 62, 247?254 (1996). 5. Greenberg, F. et al. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am. J. Hum. Genet. 49, 1207?1218 (1991). 6. Guzzetta, V. et al. Somatic cell hybrids, sequence-tagged sites, simple repeat polymorphisms, and yeast artificial chromosomes for physical and genetic mapping of proximal 17p. Genomics 13, 551?559 (1992). 7. Juyal, R.C. et al. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am. J. Hum. Genet. 58, 998?1007 (1996). 8. Chen, K.-S. et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nature Genet. 17, 154?163 (1997). 9. Osborne, L.R. et al. PMS2-related genes flank the rearrangement breakpoints associated with Williams syndrome and other diseases on human chromosome 7. Genomics 45, 402?406 (1997). 10. P�rez Jurado, L.A., Peoples, R., Kaplan, P., Hamel, B.C.J. & Francke, U. Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of- origin effects on growth. Am. J. Hum. Genet. 59, 781?792 (1996). 11. P�rez Jurado, L.A. et al. A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum. Mol. Genet. 7, 325?334 (1998). 12. Christian, S.L., Fantes, J.A., Mewborn, S.K., Huang, B. & Ledbetter, D.H. Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11?q13). Hum. Mol. Genet. 8, 1025?1037 (1999). 13. Amos-Landgraf, J.M. et al. Chromosome breakage in Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet. 65, 370?386 (1999). 14. Edelmann, L., Pandita, R.K. & Morrow, B.E. Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am. J. Hum. Genet. 64, 1076?1086 (1999). 15. Edelmann, L. et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet. 8, 1157?1167 (1999). 16. Patel, P.I. et al. The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nature Genet. 1, 159?165 (1992). 17. Chen, K.-S. et al. The human homologue of the Drosophila melanogaster flightless-I gene (fliI) maps within the Smith-Magenis microdeletion critical region in 17p11.2. Am. J. Hum. Genet. 56, 175?182 (1995). 18. Elsea, S.H. et al. Definition of the critical interval for Smith-Magenis syndrome. Cytogenet. Cell Genet. 79, 276?281 (1997). 19. Zhao, Q., Chen, K.-S., Bejjani, B.A. & Lupski, J.R. Cloning, genomic structure, and expression of mouse ring finger protein gene Znf179. Genomics 49, 394?400 (1998). 20. Roa, B.B. et al. Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1A neuropathy. Hum. Genet. 97, 642?649 (1996). 21. Kozma, C., Meck, J.M., Loomis, K.J. & Galindo, H.C. De novo duplication of 17p [dup(17)(p12?p11.2)]: report of an additional case with confirmation of the cytogenetic, phenotypic, and developmental aspects. Am. J. Med. Genet. 41, 446?450 (1991). 22. Lopes, J. et al. Sex-dependent rearrangements resulting in CMT1A and HNPP. Nature Genet. 17, 136?137 (1997). 23. Buiting, K. et al. Expressed copies of the MN7 (D15F37) gene family map close to the common deletion breakpoints in the Prader-Willi/Angelman syndromes. Cytogenet. Cell Genet. 81, 247?253 (1998). 24. Repetto, G.M., White, L.M., Bader, P.J., Johnson, D. & Knoll, J.H.M. Interstitial duplications of chromosome region 15q11q13: clinical and molecular characterization. Am. J. Med. Genet. 79, 82?89 (1998). 25. Shaffer, L.G., Kennedy, G.M., Spikes, A.S. & Lupski, J.R. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am. J. Med. Genet. 69, 325?331 (1997). 26. Pentao, L., Wise, C.A., Chinault, A.C., Patel, P.I. & Lupski, J.R. Charcot-Marie- Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nature Genet. 2, 292?300 (1992). 27. Potocki, L. et al. DNA rearrangements on both homologues of chromosome 17 in a mildly delayed individual with a family history of autosomal dominant carpal tunnel syndrome. Am. J. Hum. Genet. 64, 471?478 (1999). tems). We carried out PCR in a final volume of 50 �l containing genomic DNA (200 ng), Tris (10 mM, pH 8.3), KCl (50 mM), MgCl 2 (1.5 mM), 0.001% gelatin, dNTPs (250 �M each; Boehringer), primers (0.4 �M each), AmpliTaq (2 U; Perkin Elmer) and 10% DMSO (D17S2206 and D17S2207 only). Initial denaturation was at 95 o C for 5 min followed by 35 cycles of denaturation at 95 o C for 30 s, annealing at 55 o C for 30 s, extension at 72 o C for 30 s and a final extension at 72 o C for 7 min. Genotypes were analysed according to the manual of Linkage Mapping Set (Applied Biosystems). We visualized PCR products by 2% agarose electrophoresis and diluted 5?20 times according to the band intensity. We mixed PCR products (1.5 �l) with formamide loading dye and TAMRA 500 markers (Applied Biosystems), and electrophoresed on 5% denaturing polyacrylamide gel in the model 377-96 DNA sequencer (Applied Biosystems). Their sizes and relative inten- sities were calculated with Genescan (ver. 2.1) and Genotyper (ver. 2.0) soft- ware (Applied Biosystems). For the quantitative analysis of four polymor- phic markers within the SMS common deletion region, we performed 20?25 cycle PCR and compared the height ratios of upper and lower alleles of each genotype with those of the normal control with the same genotype. Somatic cell hybrids. We carried out polyethylene glycol fusion between the lymphoblastoid cell line from duplication 17p11.2 patient 990 and a thymi- dine kinase-deficient (TK ? ) hamster cell line, A23 (ref. 6). For this fusion, 24 independent clones were isolated with cloning rings and transferred to a 24- well microtitre plate. We obtained cells representing each clone by trypsinization of a confluent well of a 24-well plate, transferred them to a 6- well plate and then to T25 flasks. Two-colour FISH was used to analyse the hybrids and identify those retaining the 17p11.2 duplication chromosome. Acknowledgements We thank the patients and their families for participation, and A.L. Beaudet and S.M. Rosenberg for reviewing the manuscript. This work was supported in part by grants from the National Institute of Child Health and Development (NIH, K08HD01149; L.P.), the National Cancer Institute (P01CA75719; J.R.L.), the Baylor College of Medicine Mental Retardation Research Center (HD2406402), the Baylor Child Health Research Center (HD94021) and the Texas Children?s Hospital General Clinical Research Center (M01RR00188). Received 24 August; accepted 12 November 1999. � 2000 Nature America Inc. ? http://genetics.nature.com � 2000 Nature America Inc. ? http://g enetics.nature .com "
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