WO2000047770A1 - Locus de susceptibilite de l'osteoarthrite - Google Patents

Locus de susceptibilite de l'osteoarthrite Download PDF

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Publication number
WO2000047770A1
WO2000047770A1 PCT/GB2000/000493 GB0000493W WO0047770A1 WO 2000047770 A1 WO2000047770 A1 WO 2000047770A1 GB 0000493 W GB0000493 W GB 0000493W WO 0047770 A1 WO0047770 A1 WO 0047770A1
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Prior art keywords
susceptibility
osteoarthritis
polymorphic markers
identifying
region
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PCT/GB2000/000493
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English (en)
Inventor
Bryan Sykes
John Loughlin
Andrew Carr
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Catalyst Biomedica Ltd.
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Priority claimed from GBGB9903442.3A external-priority patent/GB9903442D0/en
Priority claimed from GBGB9903441.5A external-priority patent/GB9903441D0/en
Priority claimed from PCT/GB1999/003264 external-priority patent/WO2000020631A1/fr
Priority claimed from PCT/GB1999/003267 external-priority patent/WO2000020632A1/fr
Priority claimed from GBGB9926416.0A external-priority patent/GB9926416D0/en
Application filed by Catalyst Biomedica Ltd. filed Critical Catalyst Biomedica Ltd.
Publication of WO2000047770A1 publication Critical patent/WO2000047770A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • This invention relates to the identification of chromosomal regions on chromosome 6 linked to genetic sequences which affect susceptibility to osteoarthritis.
  • Osteoarthritis is a debilitating disease involving degeneration of the articular cartilage of synovial joints 5,6 .
  • OA Osteoarthritis
  • early-onset forms of the disease are associated with several osteochondrodysplasias, rare diseases involving abnormal bone and cartilage development that are transmitted as Mendelian traits 7 .
  • the OA in these conditions is secondary to the main dysplastic phenotype.
  • the common late-onset form of the disease idiopathic OA
  • Twin and segregation studies demonstrate the role of genetics in the development of the disease, with estimates of the eritability of OA of the hand, knee and hip ranging from 36% to 68% x ' 9 ' 24 .
  • association mapping has been used in over a dozen examples of rare single gene traits, and particularly in genetically isolated populations such as Finland to fine map disease mutations. Nevertheless, association mapping is fundamentally different from straightforward linkage mapping because even though the degree of association between two markers or a marker and a disease mutation is proportional to the physical distance along the chromosome this relationship can be unpredictable because it is dependent on the allele frequencies of the markers, the history of the population and the age and number of mutations at the disease locus . For rare, highly penetrant single gene diseases there is usually one major founder chromosome in the population under study, making it relatively feasible to locate an interval that is smaller than one that can be defined by standard recombination events within living families.
  • the resolution of this method in monogenic diseases in which there is one main founder chromosome is certainly less than 2cM, and in certain examples the resolution is down to 100 kb of DNA (Hastbacka et al . (1994) Cell 78,1-20).
  • the present inventors have identified a region on chromosome
  • This region was identified following a two-stage non- parametric linkage analysis.
  • the first stage involved a random screen of the genome using 272 microsatellite markers in 297 OA families.
  • the second stage was more selective and involved genotyping an additional 184 families for those markers that demonstrated moderate evidence of linkage in stage 1. This revealed three micro satellites on chromosome 11 and one on chromosome 2 for which the evidence for linkage increased as the number of families studied increased.
  • Chromosome 6 has suggested evidence of linkage in hip-only pairs with a MLS of 2.1 between D6S257 and D6S262. Over 50cM of this chromosome has a MLS > 1.5 in this stratum. This region of the genome encompasses the C0L9A1 gene (6ql2-6ql3) . We have demonstrated suggestive linkage of this gene to OA in families with hip-only disease and in female-hip pairs who were drawn from our cohort of 481 families. COL9A1 maps within the 11 cM between D6S257 and D6S286 and encodes the ⁇ l chain of type IX collagen. This collagen is a quantitatively minor heterotrimeric FACIT collagen found in cartilage 20 .
  • Type IX collagen decorates and interacts with the type II collagen fibrils.
  • Two mouse models have demonstrated that this gene is essential for normal cartilage development and that mutations result in an OA phenotype .
  • a truncated form of the gene resulted in a mild osteo- chondrodysplasia with OA 25 whilst in the second model, a knock-out mouse had no congenital abnormality but developed a severe OA that was comparable in timing and pathology to human primary OA 22 .
  • COL9A1 is therefore a strong candidate for OA and should be analysed by association analysis for potential predisposing DNA variants .
  • COL9A2 and COL9A3 map to chromosomes lp32 and 20ql3.3, respectively. There was no evidence of linkage to these two chromosomal regions in any of the six strata that we tested. Furthermore, we had previously targeted COL9A2 as a candidate locus but did not obtain evidence for linkage. It is possible that COL9A2 and COL9A3 are susceptibility genes but are not, by chance, of major impact in the cohort we have screened. Alternatively, COL9A1 may be the only type IX collagen gene that is an OA susceptibility gene.
  • the ⁇ l(IX) chain is distinct from the ⁇ 2(IX) and ⁇ 3(IX) chains in that it contains a large cartilage- specific NC4 domain that interacts with additional molecules if the extracellular matrix. This may be a site harbouring OA susceptibility.
  • ORFs Open reading frames
  • EST Expressed Sequence Tag
  • Host gopher . hcm ⁇ p .mrc .ac.uk
  • Port 70 or URL: gopher : //gopher .hgmp.mrc. ac.us : 70/ or by anonymous ftp from ftp
  • a region which is described as 'adjacent' to a microsatellite locus may be within about 1000Kb of the microsatellite, preferably within about 500Kb away, and more preferably within about 100Kb of the microsatellite.
  • Cytogenetic positions on chromosomes are referenced according to international convention (see Paris Convention 1971) .
  • the arms of a chromosome are designated p and q and each arm is then divided into sections which are given numbers .
  • the sections are then subdivided, with each subsection also being numbered. Sub-sections may be sub-divided further. Regions of a chromosome can be referenced by quoting the chromosome number, the arm and then the section and sub-section numbers.
  • polymorphic markers in the chromosomal region from 6p21.1 to 6q22.1 are known and are suitable for use in methods of the present invention. Especially preferred examples include D6S1610,D6S257, D6S286, D6S462 and D6S262. However, those of skill in the art will appreciate that other microsatellite markers within this chromosomal region may be used in an equivalent manner to that described herein for these preferred markers. Similarly, single nucleotide polymorphisms (SNPs) within the region may be used as markers in an equivalent manner.
  • SNPs single nucleotide polymorphisms
  • a first aspect of the present invention is a method for identifying individuals susceptible to osteoarthritis comprising obtaining a sample of genomic DNA and analysing alleles of polymorphic markers located in the chromosomal region from 6p21.1 to 6q22.1.
  • Another aspect of the present invention is a method for identifying individuals susceptible to osteoarthritis of the hip comprising obtaining a sample of genomic DNA and analysing alleles of polymorphic markers located in the chromosomal region from 6p21.1 to 6q22.1.
  • Another aspect of the present invention is a method for isolating genetic loci associated with susceptibility to OA comprising screening genomic libraries with genetic sequence derived from polymorphic markers located in the chromosomal region from 6p21.1 to 6q22.1 and identifying open reading frames in regions adjacent to said genetic sequence.
  • Another aspect of the present invention is a method for isolating genetic loci associated with susceptibility to OA comprising screening genomic libraries with a polymorphic markers located in the chromosomal region from 6p21.1 to 6q22.1 and identifying open reading frames located within 500 Kb, preferably within 100 Kb, more preferably within 50 Kb and most preferably within 10 Kb of the marker.
  • Another aspect of the present invention is a method for isolating genetic loci associated with susceptibility to OA comprising screening genomic libraries with genetic sequence derived from any one of the polymorphic marker D6S1610,D6S257, D6S286, D6S462 and D6S262 and identifying open reading frames in adjacent regions.
  • Another aspect of the present invention is a method for isolating genetic loci associated with susceptibility to OA comprising screening genomic libraries with any one of the polymorphic markers D6S1610,D6S257, D6S286, D6S462 and D6S262 and identifying open reading frames located within 500 Kb, preferably within 100 Kb, more preferably within 50 Kb and most preferably within 10 Kb of the marker
  • Another aspect of the present invention is the use of alleles of polymorphic markers located in chromosomal region from 6p21.1 to 6q22.1 as markers for the identification of loci influencing susceptibility to OA.
  • Another aspect of the present invention is the use of alleles of polymorphic markers located in chromosomal region from 6p21.1 to 6q22.1 as markers for the ancestral DNA variant conferring enhanced OA susceptibility.
  • Another aspect of the present invention is the use of alleles of polymorphic markers located in chromosomal region from 6p21.1 to 6q22.1 as markers for mapping associated loci to identify genes associated with OA susceptibility.
  • Another aspect of the present invention is the use of alleles of polymorphic markers located in chromosomal region from
  • Another aspect of the present invention is a method for mapping loci which affect susceptibility to OA by comparing a genomic region containing a particular allele of a polymorphic marker located in chromosomal region from 6p21.1 to 6q22.1 with a genomic region containing a different allele of the same marker.
  • Another aspect of the present invention is the use of alleles of any one of the polymorphic markers D6S1610,D6S257 , D6S286, D6S462 and D6S262 and D16S261 as a marker for the identification of loci influencing susceptibility to OA.
  • Another aspect of the present invention is the use of alleles of any one of the polymorphic markers D6S1610,D6S257 , D6S286, D6S462 and D6S262 as a marker for the ancestral DNA variant conferring enhanced OA susceptibility.
  • Another aspect of the present invention is the use of alleles of any one of the polymorphic markers D6S1610, D6S257, D6S286, D6S462 and D6S262 as a marker for mapping associated loci to identify genes associated with OA susceptibility.
  • Another aspect of the present invention is the use of alleles of any one of the polymorphic markers D6S1610 , D6S257 , D6S286, D6S462 and D6S262 in investigating loci capable of influencing susceptibility to OA.
  • Another aspect of the present invention is a method for mapping loci which affect susceptibility to OA by comparing a genomic region containing a particular allele of any one of the polymorphic markers D6S1610 , D6S257 , D6S286, D6S462 and D6S262 with a genomic region containing a different allele of the same marker.
  • Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising a polymorphic marker located in chromosomal region from 6p21.1 to 6q22.1, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
  • LOD maximum log of the odds
  • Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising any one of the polymorphic markers D6S1610 , D6S257 , D6S286, D6S462 and D6S262, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
  • LOD maximum log of the odds
  • Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising a polymorphic marker and located within 20cM, preferably within 15 cM, or more preferably within lOcM, even more preferably within 5cM and most preferably within 2cM, of any one of the polymorphic markers D6S1610,D6S257, D6S286, D6S462 and D6S262, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1 and a p-value of less then 0.25, and determining individual susceptibility to osteoarthritis by reference to the allele sharing.
  • LOD maximum log of the odds
  • Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising obtaining sample genomic DNA from siblings, at least two of which have clinical symptoms of osteoarthritis. analysing a region of their genomic DNA comprising one or more of the polymorphic markers D6S1610,D6S257, D6S286, D6S462 and D6S262 and additionally analysing one or more genomic regions comprising the polymorphic markers; D2S202, D2S325, D2S117, D3S1266, D4S415, D4S398, D4S231, D4S250, D4S406, D6S260, D6S273, D6S286, D6S281, D7S669, D7S530, D11S937, D11S907, D11S903, D11S901, D17S807, D17S789 and DXS1068, identifying allele sharing between the siblings as defined by a maximum log of the odds (LOD) score of greater than 1
  • Another aspect of the present invention is a method for isolating genetic loci associated with susceptibility to OA comprising screening a genomic library with sequence derived from the region between polymorphic markers D6S1610 and D6S262 and identifying those isolated clones which additionally contain open reading frames
  • Another aspect of the present invention is a method for isolating genetic loci associated with susceptibility to OA comprising screening a genomic library with sequence derived from the region between polymorphic markers D6S257 and D6S262 and identifying those isolated clones which additionally contain open reading frames.
  • Another aspect of the present invention is a method for isolating genetic loci associated with susceptibility to OA comprising screening a genomic library with sequence derived from the region between polymorphic markers D6S257 and D6S286 and identifying those isolated clones which additionally contain open reading frames .
  • Another aspect of the present invention is a method for identifying loci conferring susceptibility to osteoarthritis comprising screening a genomic library with genetic sequence derived from one or more of the polymorphic markers D6S1610,D6S257, D6S286, D6S462 and D6S262 and identifying open reading frames located within 500 Kb, more preferably within 100 Kb, even more preferably within 50 Kb or most preferably within 10 Kb of any of these polymorphic markers .
  • Another aspect of the present invention is a method for identifying individuals susceptible to osteoarthritis comprising obtaining a sample of genomic DNA and analysing the COL9A1 gene for the presence of alleles associated with OA susceptibility.
  • Another aspect of the present invention is a method for determining individual susceptibility to osteoarthritis comprising sequencing the COL9A1 gene, identifying the allelic form of the gene, correlating the allelic form of the sequenced gene to the known susceptibility to OA of individuals with that allelic form.
  • such an individual may be one who has OA, is considered at risk from OA (e.g. by having a sibling with and/or fai ily history of OA) , or may be symptomless.
  • the DNA sample from the individual may be prepared from any convenient sample, for example from blood or skin tissue.
  • the present invention relates to screening for genetic loci, including ORFs, related to OA
  • such screening is generally performed on a population sample.
  • the sample includes individuals with and without OA. More desirably the sample comprises at least a proportion of sibling pairs or larger cohorts.
  • at least 100, preferably at least 500 or more preferably at least 1000 individuals may be sampled.
  • Preferably at least 30%, preferably at least 50% and more preferably at least 70% will exhibit symptoms of OA.
  • the analysis of the individuals may be stratified with respect to a number of factors, such as sex, severity, location or age of onset of disease, and the like.
  • a further aspect of the invention provides isolated nucleic acid comprising the ORF, the use of the ORF in the diagnosis or prognosis of OA, a polypeptide in isolated form encoded by the ORF and the use of the polypeptide in methods of diagnosis or prognosis of OA.
  • Nucleic acid comprising the ORF will generally be in the form of a recombinant replicable vector, in which nucleic acid, in the form of RNA or DNA, consisting of the ORF is operably linked to a promoter.
  • the nucleic acid may optionally include 5 ' or 3' regions to the ORF containing such things as signal sequences, tags such as polyhistidine tags to allow isolation of expressed product, 5' or 3 ' untranslated regions, and the like.
  • the promoter will be selected to be compatible with a desired host cell, such as a bacterial, yeast, insect or mammalian host cell.
  • the vector may be constructed by conventional means in the art, for example by providing a pair of PCR primers to a sample of mRNA or genomic DNA, which primer pair is suitable to amplify up the ORF from the sample.
  • the primers may incorporate restriction enzyme sites to facilitate insertion of amplified product into a suitable vector.
  • Various expression vectors are readily available in the art from commercial sources .
  • Host cells may be used for the production of a protein encoded by the ORF by introducing the expression vectors into the host cell.
  • the host cells may be cultivated using standard techniques known as such in the art under conditions! to bring about expression of the protein encoded by the ORF, and the protein recovered from the host cell or its culture medium.
  • Antibodies such as monoclonal, polyclonal or synthetic (e.g. from a phage display library) may be raised or selected against the protein.
  • the term “anitbodies” includes binding fragments thereof, such as Fab and Fv (including scFv) fragments .
  • ORF nucleic acid, proteins encoded by it, and antibodies thereto may be used in the diagnosis or prognosis of OA.
  • the presence of alleles of the nucleic acid in subjects with or without OA may be determined, the levels of expression of nucleic acid or the amount of protein present in cells in such subjects may also be determined. Such determination may be used to link the presence of alleles of
  • ORFs or the presence or absence of particular threshold levels of expression or protein production, to the diagnosis or prognosis of OA.
  • Figure 1 shows a multipoint log of the odds (LOD) analysis of chromosome 6 using stratified data.
  • the analysis shows an MLS score of about 2 for the hip only category in the region between markers D6S1610 and D4S314 and an MLS score of about 1 for the female hip category in the region between D6S422 and D6S265.
  • the present inventors collected 481 families in which at least two siblings have undergone joint replacement surgery of the hip or knee for severe, end-stage idiopathic OA (Table 1) . Due to the late onset of the disease, none of these families contained parents who could participate in the study. In stage 1 272 microsatellite markers were genotyped in 297 of the 481 families. The microsatellites were essentially those used by Reed et al 8 with the replacement of certain markers that amplified unreliably. Sixteen markers from stage 1 had evidence of linkage at p ⁇ 0.05 (Table 2) . These markers were then genotyped in the remaining 184 families.
  • We adjusted MLS values to correct for the six strata tested by deducting log7 0.8 from the original values 23 .
  • Over 50 cM of chromosome 6 has a corrected MLS > 1.5 in the hip-only strata. This region is encompassed by D6S257 and D6S262.
  • the female-hip strata also has a corrected MLS > 1.0 on chromosome 6, with an MLS of 1.0 between D6S422 and D6S265. This region encompasses the HLA gene cluster on 6p21.3.
  • the suggestive linkage indicates that this region harbours a susceptibility locus for OA.
  • Families were recruited which contained at least two siblings two had undergone one or more total hip (THR) and/or total knee replacements (TKR) for idiopathic OA. Clinically these patients are at the severe end of the OA spectrum with advanced radiological changes. The idiopathic diagnosis was supported by clinical, radiological, operative and histological findings: patients who had undergone joint replacement surgery secondary to other factors, such as intra-articular fracture or rheumatoid arthritis, were excluded. Families were ascertained at three centres within the United Kingdom: The Nuffield Orthopaedic Centre in Oxford, the Royal Orthopaedic Hospital in Birmingham and Musgrave Park Hospital in Harbor. Idiopathic OA is typically a late-onset disease and parents of affected siblings are rarely available.
  • THR total hip
  • TKR total knee replacements
  • the 481 families used in the study None contained a parent who was able to participate. We therefore collected siblings who had not undergone joint replacement to assist in the determination of identity-by-descent (IBD) allele transmittance .
  • the 481 families were comprised of 1052 affected individuals plus an additional 302 unaffected siblings (Table 1). 59.3% of the affected individuals were female, 40.7% were male.
  • 25ml of venous blood was collected into EDTA tubes and DNA was extracted by conventional techniques . Markers and Genotyping.
  • Non parametric linkage analysis was performed using the SIBPAIR module of the ANALYZE package 18 .
  • This module is able to use data from siblings to determine identity-by-descent (IBD) allele transmittance . In this way it is appropriate to our study since we were unable to collect parents of our affected siblings.
  • IBD identity-by-descent
  • the SIBPAIR module produces a singlepoint LOD score and its asymptotic P-value. Allele frequencies were calculated from the input data using either GAS or Downfreq (part of the ANALYZE package) . Subsequent multipoint analyses was performed using ASPEX 19 (ftp: //lahmed.
  • ASPEX produces maximum LOD score (MLS) under an additive model. In addition it produces an exclusion map along the entire chromosome based on a fixed value for A? .
  • a hip-only pair were siblings who had each undergone joint replacement of the hip only (mono or bi-lateral) whilst a knee-only pair had undergone joint replacement of the knee only (mono or bi-lateral) . If an affected pair was composed of one sibling who had undergone joint replacement of one joint type only (hip or knee) whilst their affected sibling had undergone joint replacement of the hip and knee then that pair were excluded. For an affected trio, if a pair of the siblings had both undergone joint replacement of the same joint type only (hip or knee) whilst the third sibling had undergone both hip and knee replacement, then the concordant pair were used in the stratification study whilst the third sibling was given an unaffected status in the linkage analysis. Again, we were attempting to maximise our determination of IBD allele transmittance.

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Abstract

On sait que différents locus à l'intérieur du génome jouent un rôle dans la susceptibilité que présente un individu d'être atteint d'ostéoarthrite. L'invention concerne l'identification d'une région génétique pouvant éventuellement contenir un locus de susceptibilité de l'ostéoarthrite. On a effectué une analyse des liaisons génétiques à l'échelle du génome sur des familles touchées par l'ostéoarthrite. On a stratifié les résultats en fonction du sexe et des articulations touchées. On a pu ainsi obtenir une preuve de la liaison de marqueurs sur le chromosome 6 entre 6p21.1 et 6q22, ce qui indique la présence d'un locus de susceptibilité de l'ostéoarthrite dans cette région chromosomique.
PCT/GB2000/000493 1999-02-15 2000-02-14 Locus de susceptibilite de l'osteoarthrite WO2000047770A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
GB9903442.3 1999-02-15
GBGB9903442.3A GB9903442D0 (en) 1999-02-15 1999-02-15 Susceptibilty locus
GBGB9903441.5A GB9903441D0 (en) 1999-02-15 1999-02-15 Susceptibilty locus
GB9903441.5 1999-02-15
GBPCT/GB99/03264 1999-10-04
PCT/GB1999/003264 WO2000020631A1 (fr) 1998-10-02 1999-10-04 Locus de susceptibilite lie a l'arthrose
GBPCT/GB99/03267 1999-10-04
PCT/GB1999/003267 WO2000020632A1 (fr) 1998-10-02 1999-10-04 Locus de susceptibilite a l'arthrose
GB9926416.0 1999-11-08
GBGB9926416.0A GB9926416D0 (en) 1999-02-15 1999-11-08 Susceptibility locus

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
FR2842105A1 (fr) * 2002-07-10 2004-01-16 Oreal Localisation des genes impliques dans la canitie precoce
FR2842104A1 (fr) * 2002-07-10 2004-01-16 Oreal Genes impliques dans la canitie precoce
WO2004007742A2 (fr) * 2002-07-10 2004-01-22 L'oreal Genes des chromosomes 6 et 9 impliques dans la canitie precoce
FR2853532A1 (fr) * 2003-04-08 2004-10-15 Oreal Genes des chromosomes 6 et 9 impliques dans la canitie precoce

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* Cited by examiner, † Cited by third party
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FR2842105A1 (fr) * 2002-07-10 2004-01-16 Oreal Localisation des genes impliques dans la canitie precoce
FR2842104A1 (fr) * 2002-07-10 2004-01-16 Oreal Genes impliques dans la canitie precoce
WO2004007742A2 (fr) * 2002-07-10 2004-01-22 L'oreal Genes des chromosomes 6 et 9 impliques dans la canitie precoce
WO2004007764A2 (fr) * 2002-07-10 2004-01-22 L'oreal Genes des chromosomes 3,5 et 11 impliques dans la canitie precoce
WO2004007764A3 (fr) * 2002-07-10 2004-04-08 Oreal Genes des chromosomes 3,5 et 11 impliques dans la canitie precoce
WO2004007742A3 (fr) * 2002-07-10 2004-06-17 Oreal Genes des chromosomes 6 et 9 impliques dans la canitie precoce
FR2853532A1 (fr) * 2003-04-08 2004-10-15 Oreal Genes des chromosomes 6 et 9 impliques dans la canitie precoce

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