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ABSTRACT: Das Beckwith-Wiedemann-Syndrom (BWS) ist ein pädiatrisches Überwuchssyndrom mit variablem klinischem Erscheinungsbild. Obwohl
die betroffenen Kinder mit zunehmendem Alter immer normaler aussehen, ist es wichtig, die Diagnose BWS zu stellen. Gründe
sind mögliche syndromspezifische Komplikationen, insbesondere ein 400-fach erhöhtes Risiko der Patienten, an bestimmten embryonalen
Tumoren – Nephroblastome (Wilms-Tumoren), Hepatoblastome u.a. – innerhalb der ersten Lebensjahre zu erkranken. Klinisch überlappt
das BWS mit anderen Krankheitsentitäten, sodass eine eindeutige molekulargenetische Diagnostik zur Risikoabschätzung und adäquaten
Therapie wünschenswert ist. Molekular ist das BWS mit der Chromosomenregion 11p15.5 assoziiert, einer Region in der es 2Cluster
von Genen gibt, die dem genomischen Imprinting unterliegen. Bei den Patienten lassen sich Sequenzabweichungen in bestimmten
Genen finden, die Mehrzahl weisen aber DNA-Methylierungsveränderungen auf, welche die Gendosis der funktionell zur Verfügung
stehenden, monoallelisch aktiven 11p15.5-Gene pathogen beeinflussen. Zurzeit existiert nur eine sehr unvollständige Genotyp-Phänotyp-Korrelation.
Aktuelle Forschungsarbeiten liefern Ansätze, die Ätiopathogenese des Syndroms molekular besser zu verstehen. So werden beispielsweise
Interaktionspartner identifiziert, die das Imprinting der 11p15.5-Gene modifizieren und epigenetisch regulieren.
The Beckwith-Wiedemann syndrome (BWS) is a pediatric overgrowth syndrome with a variable clinical appearance. The phenotype
normalizes with age but the diagnosis of BWS is important as syndrome-specific complications may develop, in particular as
a result of a 400-fold increased risk of patients developing certain tumor entities, predominantly nephroblastomas (Wilms’
tumors) and hepatoblastomas, within the first years of life. BWS displays a clinical overlap with other syndromes so that
an unambiguous molecular diagnostic is required for risk assessment and appropriate therapy. At the molecular level BWS is
associated with the chromosomal region 11p15.5, where two clusters with imprinted genes are located. In patients both genetic
mutations and in most cases aberrant DNA methylation can be observed, which pathogenically affect the gene dosage of functionally
available monoallelically expressed 11p15.5 genes. Currently only a very incomplete genotype-phenotype correlation exists
for BWS. Current research projects provide insights in the molecular etiopathogenesis of the syndrome by identifying interacting
partners which modify the epigenetic regulation of imprinted 11p15.5-genes.
SchlüsselwörterBeckwith-Wiedemann-Syndrom-Überwuchs-Wilms-Tumor-Gene-Humanes IGF2-Protein-Genomisches Imprinting
KeywordsBeckwith-Wiedemann syndrome-Gigantism-Wilms’ tumor genes-IGF2 protein, human-Genomic imprinting
Medizinische Genetik 04/2012; 22(4):399-404. · 0.06 Impact Factor
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J Dai,
O-H Kim,
T-J Cho,
M Schmidt-Rimpler,
H Tonoki,
K Takikawa,
N Haga,
K Miyoshi,
H Kitoh,
W-J Yoo, [......],
A Mustonen,
Q Jiang,
H Ohashi,
T Furuichi,
S Unger, B Zabel,
E Lausch,
A Superti-Furga,
G Nishimura,
S Ikegawa
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ABSTRACT: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear.
To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands.
TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations.
The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.
Journal of Medical Genetics 10/2010; 47(10):704-9. · 6.36 Impact Factor
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J G Hengstler,
E O Bockamp,
M Hermes,
M Brulport,
A Bauer,
W Schormann,
I B Schiffer,
C Hausherr,
L Eshkind,
C Antunes,
A Franzen,
K Krishnamurthi,
E Lausch,
R Lessig,
T Chakrabarti,
D Prawitt, B Zabel,
C Spangenberg
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ABSTRACT: Identification of oncogene dependent signaling pathways controlling aggressive tumor growth has led to the emergence of a new era of oncogene-blocking therapies, including Herceptin and Gleevec. In the recent years conditional mouse tumor models have been established that allow switching-off the expression of specific oncogenes controlling tumor growth. The results may have two important implications for oncogene-blocking therapies: (i) downregulation of oncogenes, for instance HER2, MYC, RAS, RAF, BCR-ABL or WNT1, usually leads to a rapid tumor remission. However, it was observed that the initial remission was followed by recurrent tumor growth in most studies. Interestingly, different oncogenes controlled tumor growth in the recurrent than in the primary tumors. This could explain the astonishing clinical observation that inhibitors of a broader spectrum of protein kinases (so-called: "dirty inhibitors") may be superior over highly specific substances. Due to their additional "unspecific" inhibition of a broader spectrum of kinases, they may hamper the escape mechanisms by antagonizing also the pathways controlling recurrent tumor growth. (ii) Experiments with cell systems that allow switching-on oncogene expression point to a so far possibly underestimated cancer drug target: the dormant tumor cell. Oncogene expression (for instance: NeuT or RAS) led to a phenomenon named oncogene-induced senescence or dormancy. Dormant cells are unresponsive to mitogenic stimuli. Importantly, such cells are not at all ready to die, but can remain viable for extended periods of time. Recently, dormant tumor cells have been shown to be more resistant to stresses such as hypoxia or exposure to cytostatic drugs. It still is a matter of debate if and under which conditions dormant tumor cells can be "kissed to life". If these cells contribute to carcinogenesis, it will be important to identify substances specifically killing senescent cells. This review will focus on the possible relevance of senescence both as a pre-oncogenic condition and also for therapy.
Current cancer drug targets 12/2006; 6(7):603-12. · 5.13 Impact Factor
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ABSTRACT: Pseudoachondroplasia (PA) is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature, generalized ligamentous laxity, irregular epi-metaphyseal ossification, and vertebral anomalies that regress with age. It usually manifests in the second year of life or later. The clinically and radiographically variable disorder is caused by mutations in the COMP gene. Parental gonadal mosaicism may lead to recurrence of the disorder in children of unaffected parents. Here, we describe sibs with bone changes similar to those seen in very severe PA born to clinically and radiographically unaffected parents. Sequencing of all 19 exons of the COMP gene failed to disclose a mutation. The sibs appear to be affected by a disorder resembling PA but resulting from a defect of an extracellular matrix protein other than COMP. It may be suspected in patients with unusually severe dwarfism, severe epi-metaphyseal abnormalities, and persistent platyspondyly.
American Journal of Medical Genetics Part A 02/2005; 132A(1):20-4. · 2.39 Impact Factor
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[show abstract]
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ABSTRACT: Pseudoachondroplasia (PA) is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature, generalized ligamentous laxity, irregular epi-metaphyseal ossification, and vertebral anomalies that regress with age. It usually manifests in the second year of life or later. The clinically and radiographically variable disorder is caused by mutations in the COMP gene. Parental gonadal mosaicism may lead to recurrence of the disorder in children of unaffected parents. Here, we describe sibs with bone changes similar to those seen in very severe PA born to clinically and radiographically unaffected parents. Sequencing of all 19 exons of the COMP gene failed to disclose a mutation. The sibs appear to be affected by a disorder resembling PA but resulting from a defect of an extracellular matrix protein other than COMP. It may be suspected in patients with unusually severe dwarfism, severe epi-metaphyseal abnormalities, and persistent platyspondyly. © 2004 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 12/2004; 132A(1):20 - 24. · 2.39 Impact Factor
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K Eger,
M Hermes,
K Uhlemann,
S Rodewald,
J Ortwein,
M Brulport,
A W Bauer,
W Schormann,
F Lupatsch,
I B Schiffer, [......],
C Sauer,
B Tanner,
H Kolbl,
U Krugel,
H Franke,
P Illes,
P Madaj-Sterba,
E O Bockamp,
T Beckers,
J G Hengstler
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ABSTRACT: Since the pioneering work by Gossen and Bujard in 1992 demonstrating the usefulness of the Escherichia coli derived tet resistance operon for regulating gene expression a large collection of doxycycline-controlled transgenic mice has been established. Gene switching in eukaryotic tissue culture cells or mice requires administration of tetracycline, anhydrotetracycline or doxycycline to efficiently inactivate the transactivator protein tTA (TET-OFF system) or alternatively to activate the reverse transactivator protein rtTA (TET-ON system). However, the antibiotic activity of doxycycline can create an imbalance of the intestinal flora, resulting in diarrhoea and in a smaller number of animals in colitis. Previous studies reported that 4-epidoxycycline (4-ED), a hepatic metabolite of doxycycline, does not function as an antibiotic in mice. This gave us the idea that 4-ED might be useful for controlling gene expression in mice without the unwanted antibiotic side effect. To study the applicability of 4-ED for control of gene expression we used cell lines expressing the oncogene HER2 under control of tTA (TET-OFF) as well as rtTA (TET-ON). 4-ED and doxycycline were similarly efficient in switching on or -off HER2 expression. In vivo we used a conditional mouse model that allows switching off HER2 in tumor tissue. We show that (i) doxycycline, 7.5mg/ml in drinking water (used as a positive control), (ii) 4-ED, 7.5mg/ml in drinking water, (iii) 4-ED, 10mg/kg body weight, s.c., and (iv) anhydrotetracycline, 10mg/kg, s.c. (used as a second positive control), were similarly efficient. Using mice with tumor volumes of 1.6cm(3) all four schedules led to a tumor remission of more than 95% within 7 days. In conclusion, 4-ED is similarly efficient as doxycycline to control gene expression in vitro and in mice. Since 4-ED lacks the antibiotic activity of doxycycline it may help to avoid adverse side effects and selection of resistant bacteria.
Biochemical and Biophysical Research Communications 11/2004; 323(3):979-86. · 2.48 Impact Factor
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ABSTRACT: RNA interference (RNAi) has been extensively used for sequence-specific silencing of gene function in mammalian cells. The latest major breakthrough in the application of RNAi technology came from experiments demonstrating RNAi-mediated gene repression in mice and rats. After more than two decades of functional mouse research aimed at developing and continuously improving transgenic and knock-out technology, the advent of RNAi knock-down mice represents a valuable new alternative for studying gene function in vivo. In this review we provide some basic insight as to how RNAi can induce gene silencing to then focus on recent findings concerning the applicability of RNAi for regulating gene function in the mouse. Reviewed topics will include delivery methods for RNAi-mediating molecules, a comparison between traditional knock-out and innovative transgenic RNAi technology and the generation of graded RNAi knock-down phenotypes. Apart from the exciting possibilities RNAi provides for studying gene function in mice, we discuss several caveats and limitations to be considered. Finally, we present prospective strategies as to how RNAi technology might be applied for generating conditional and tissue-restricted knock-down mice.
Cytogenetic and Genome Research 02/2004; 105(2-4):412-21. · 1.53 Impact Factor
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D Ballhausen,
L Bonafé,
P Terhal,
S L Unger,
G Bellus,
M Classen,
B C Hamel,
J Spranger, B Zabel,
D H Cohn,
W G Cole,
J T Hecht,
A Superti-Furga
Journal of Medical Genetics 02/2003; 40(1):65-71. · 6.36 Impact Factor
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Y Gong,
R B Slee,
N Fukai,
G Rawadi,
S Roman-Roman,
A M Reginato,
H Wang,
T Cundy,
F H Glorieux,
D Lev, [......],
W Swoboda,
M J van den Boogaard,
W Van Hul,
M Vikkula,
M Votruba, B Zabel,
T Garcia,
R Baron,
B R Olsen,
M L Warman
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ABSTRACT: In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
Cell 12/2001; 107(4):513-23. · 32.40 Impact Factor
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ABSTRACT: Characterisation of chromosome rearrangements using conventional banding techniques often fails to determine the localisation of breakpoints precisely. In order to improve the definition of chromosomal breakpoints, the high-resolution multicolour banding (MCB) technique was applied to identify human chromosome 5 breakpoints from 40 clinical cases previously assessed by conventional banding techniques. In 30 cases (75%), at least one breakpoint was redefined, indicating that MCB markedly improves chromosomal breakpoint localisation. The MCB pattern is highly reproducible and, in contrast to conventional banding pattern, is consistent in both short and elongated chromosomes. This might be of fundamental interest for the detection of chromosomal abnormalities, especially in tumour cells. Moreover, MCB even allows the detection of abnormalities that remain cryptic in GTG-banding analysis.
Human Genetics 07/2001; 108(6):478-83. · 5.07 Impact Factor
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R Morello,
G Zhou,
S D Dreyer,
S J Harvey,
Y Ninomiya,
P S Thorner,
J H Miner,
W Cole,
A Winterpacht, B Zabel,
K C Oberg,
B Lee
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ABSTRACT: Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.
Nature Genetics 03/2001; 27(2):205-8. · 35.53 Impact Factor
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H J Lüdecke,
J Schaper,
P Meinecke,
P Momeni,
S Gross,
von Holtum D,
H Hirche,
M J Abramowicz,
B Albrecht,
C Apacik, [......],
K H Orstavik,
E Plöchl,
C Seitz,
J Schmidtke,
L Tranebjaerg,
M Tsukahara,
B Wittwer, B Zabel,
G Gillessen-Kaesbach,
B Horsthemke
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ABSTRACT: Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.
The American Journal of Human Genetics 02/2001; 68(1):81-91. · 10.60 Impact Factor
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ABSTRACT: Multiple epiphyseal dysplasia (MED) is an osteochondrodysplasia characterized clinically by mild short stature and early-onset degenerative joint disease and radiographically by epiphyseal hypoplasia/dysplasia. MED is genetically heterogeneous, with autosomal dominant cases resulting from mutations in at least three genes: the cartilage oligomeric matrix protein (COMP) gene (EDM1) and the COL9A2 (EDM2) and COL9A3 (EDM3) genes of type IX procollagen. We present here a comparison of the radiographic phenotypes of MED patients with type IX collagen gene mutations and those with COMP gene mutations. We reviewed radiographs from two patients with MED produced by COMP mutations, two families with COL9A2 mutations, and one family with a mutation in COL9A3. The data demonstrated that the patients with type IX collagen defects had more severe joint involvement at the knees and relative hip sparing, while the patients with COMP mutations had significant involvement at the capital femoral epiphyses and irregular acetabuli. This pattern of joint involvement was consistent regardless of overall degree of severity of the phenotype.
Pediatric Radiology 02/2001; 31(1):10-8. · 1.67 Impact Factor
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ABSTRACT: Comparative genomic hybridization (CGH) has been applied to characterize 61 primary renal cell carcinomas derived histogenetically from the proximal tubulus. The tumor samples comprised 46 clear-cell renal cell carcinomas (ccRCCs) and 15 papillary renal cell carcinomas (pRCCs). Changes in the copy number of entire chromosomes or subregions were detected in 56 tumors (92%). In ccRCCs, losses of chromosome 3 or 3p (63%); 14q (30%); 9 (26%); 1 and 6 or 6q (17% each); 4 and 8 or 8p (15% each); 22 (11%); 2 or 2q and 19 (9% each); 7q, 10, 16, 17p, 18, and Y (7% each); and 5, 11, 13, 15, and 21 (4% each) were detected. Most frequent genomic gains in ccRCC were found on chromosome 5 (63%); 7 (35%); 1 or 1q (33%); 2q (24%); 8 or 8q, 12, and 20 (20% each); 3q (17%); 16 (15%); 19 (13%); 6 and 17 or 17q (11% each); and 4, 10, 11, 21, and Y (9% each). In pRCCs, gains in the copy number of chromosomes 7 and 17 (7/15, each) and 16 and 20 (6/15, each) were frequent. One pRCC showed amplification of subchromosome regions 2q22-->q33, 16q, 17q and the entire X chromosome. In pRCC, losses were less frequently seen than gains. Losses of chromosomes 1, 14, 15, and Y (3/15 each) and 2, 4, 6, and 13 (2/15 each) were observed. In ccRCCs, statistical evaluation revealed significant correlations of chromosomal imbalances with tumor stage and grade, i.e., a gain in copy number of chromosome 5 correlated positively with low tumor grade, whereas a gain of chromosomes 10 and 17 correlated positively with high tumor grade. Furthermore, loss of chromosome 4 correlated positively with high tumor stage.
Cytogenetics and cell genetics 02/2001; 93(3-4):221-7.
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ABSTRACT: Comparative genomics is a superior way to identify phylogenetically conserved features like genes or regions involved in gene regulation. The comparison of extended orthologous chromosomal regions should also reveal other characteristic traits essential for chromosome or gene function. In the present study we have sequenced and compared a region of conserved synteny from human chromosome 11p15.3 and mouse chromosome 7. In human, this region is known to contain several genes involved in the development of various disorders like Beckwith-Wiedemann overgrowth syndrome and other tumor diseases. Furthermore, in the neighboring chromosome region 11p15.5 extensive imprinting of genes has been reported which might extend to region 11p15.3. The analysis of approximately 730 kb in human and 620 kb in mouse led to the identification of eleven genes. All putative genes found in the mouse DNA were also present in the same order and orientation in the human chromosome. However, in the human DNA one putative gene of unknown function could be identified which is not present in the orthologous position of the mouse chromosome. The sequence similarity between human and mouse is higher in transcribed and exon regions than in non-transcribed segments. Dot plot analysis, however, reveals a surprisingly well-conserved sequence similarity over the entire analyzed region. In particular, the positions of CpG islands, short regions of very high GC content in the 5' region of putative genes, are similar in human and mouse. With respect to base composition, two distinct segments of significantly different GC content exist as well in human as in the mouse. With a GC content of 45% the one segment would correspond to "isochore H1" and the other segment (39% GC in human, 40% GC in mouse) to "isochore L1/L2". The gene density (one gene per 66 kb) is slightly higher than the average calculated for the complete human genome (one gene per 90 kb). The comparison of the number and distribution of repetitive elements shows that the proportion of human DNA made up by interspersed repeats (43.8%) is significantly higher than in the corresponding mouse DNA (30.1%). This partly explains why the human DNA is longer between the landmark genes used to define the orthologous positions in human and mouse.
Cytogenetics and cell genetics 02/2001; 93(3-4):284-90.
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Journal of Medical Genetics 09/2000; 37(8):627-9. · 6.36 Impact Factor
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Journal of Medical Genetics 05/2000; 37(4):318-20. · 6.36 Impact Factor
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ABSTRACT: Lmx1b, a member of the LIM homeodomain protein family, is essential for the specification of dorsal limb fates at the zeugopodal and autopodal level in vertebrates. We and others have shown that a skeletal dysplasia, nail-patella syndrome (NPS), results from mutations in LMX1B. While it is a unique mesenchymal determinant of dorsal limb patterning during vertebrate development, the mechanism by which LMX1B mutations generate the NPS phenotype has not been addressed at a transcriptional level or correlated with its spatial pattern of gene expression. In this study, in situ hybridizations of Lmx1b on murine limb sections reveal strong expression in dorsal mesenchymal tissues (precursors of muscle, tendons, joints and patella) and, interestingly, also in anterior structures of the limb, explaining the anterior to posterior gradient of joint and nail dysplasia observed in NPS patients. Transfection studies showed that both the LIM domain-interacting protein, LDB1, and the helix-loop-helix protein, E47/shPan1, can regulate LMX1B action. While co--transfections of E47/shPan1 with LMX1B result in a synergistic effect on reporter activity, LDB1 down-regulated LMX1B-mediated transactivation irrespective of E47/shPan1. Mutant LMX1B proteins containing human mutations affecting each of the helices or the N-terminal arm of the homeodomain abolished transactivation, while LIM B and truncation mutations retained residual activity. These mutations fail to act in a dominant-negative manner on wild-type LMX1B in mixing studies, thereby supporting haploinsufficiency as the mechanism underlying NPS pathogenesis.
Human Molecular Genetics 05/2000; 9(7):1067-74. · 7.64 Impact Factor
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ABSTRACT: The DmX gene was recently isolated from the X chromosome of Drosophila melanogaster. TBLASTN searches of the dbEST databases revealed sequences with a high level of similarity to DmX in a variety of different species, including insects, nematodes, and mammals showing that DmX is an evolutionarily highly conserved gene. Here we describe the cloning of the cDNA and the chromosomal localization of one of the human homologues of DmX, Dmx-like 1 (DMXL1). The human DMXL1 gene codes for a large mRNA of 11 kb with an open reading frame of 3027 amino acids. The putative protein belongs to the superfamily of WD repeat proteins, which have mostly regulatory functions. The DMXL1 protein contains an exceptionally large number of WD repeat units. The DMXL1 gene is located on chromosome 5q22 as determined by radiation hybrid mapping and fluorescence in situ hybridization. Although the function of the DMXL1 gene and its homologues in other species remains to be discovered, the high level of evolutionary conservation together with the unusual structure suggests that it probably has an important function.
Genomics 03/2000; 64(1):97-101. · 3.02 Impact Factor
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ABSTRACT: Fibroblast growth factor receptor 3 (FGFR3) is a glycoprotein that belongs to the family of tyrosine kinase receptors. Specific mutations in the FGFR3 gene are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, and thanatophoric dysplasia. Hypochondroplasia (HCH), the mildest form of this group of short-limbed dwarfism disorders, results in approximately 60% of cases from a mutation in the intracellular FGFR3-tyrosine kinase domain. The remaining cases may either be caused by defects in other FGFR gene regions or other yet unidentified genes. We describe a novel HCH mutation, the first found outside the common mutation hot spot of this condition. This point mutation, an N328I exchange in the extracellular Ig domain III of the receptor, seems to be unique as it affects a putative N-glycosylation site that is conserved between different FGFRs and species. The amino acid exchange itself most probably has no impact on the three-dimensional structure of the receptor domain, suggesting that the phenotype is the result of altered receptor glycosylation and its pathophysiological consequences.
Physiological Genomics 02/2000; 2(1):9-12. · 2.73 Impact Factor
