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Spanish families with cavernous angiomas do not share the Hispano- American CCM1haplotype
  1. H H JUNG,
  2. P LABAUGE,
  3. S LABERGE,
  4. E MARÉCHAL,
  5. E TOURNIER-LASSERVE
  1. INSERM U25, Faculté de Médecine Necker, Paris, France
  2. Laboratorio de Biologia Molecular
  3. Servicio de Neurologia, Hospital Unversitario Virgen Macarena, Avenida Dr Fedriani, 41071 Sevilla, Spain
  4. Hôpital Lariboisière, Paris, France
  1. E Tournier-Lasserve, INSERM U25, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75730 Paris Cedex 15. France, Telephone 0033 1 45 67 25 97; fax 0033 1 40 56 01 07; email: tournier{at}necker.fr
  1. M LUCAS
  1. INSERM U25, Faculté de Médecine Necker, Paris, France
  2. Laboratorio de Biologia Molecular
  3. Servicio de Neurologia, Hospital Unversitario Virgen Macarena, Avenida Dr Fedriani, 41071 Sevilla, Spain
  4. Hôpital Lariboisière, Paris, France
  1. E Tournier-Lasserve, INSERM U25, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75730 Paris Cedex 15. France, Telephone 0033 1 45 67 25 97; fax 0033 1 40 56 01 07; email: tournier{at}necker.fr
  1. J M GARCIA-MORENO,
  2. M A GAMERO,
  3. G IZQUIERDO
  1. INSERM U25, Faculté de Médecine Necker, Paris, France
  2. Laboratorio de Biologia Molecular
  3. Servicio de Neurologia, Hospital Unversitario Virgen Macarena, Avenida Dr Fedriani, 41071 Sevilla, Spain
  4. Hôpital Lariboisière, Paris, France
  1. E Tournier-Lasserve, INSERM U25, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75730 Paris Cedex 15. France, Telephone 0033 1 45 67 25 97; fax 0033 1 40 56 01 07; email: tournier{at}necker.fr
  1. E TOURNIER-LASSERVE
  1. INSERM U25, Faculté de Médecine Necker, Paris, France
  2. Laboratorio de Biologia Molecular
  3. Servicio de Neurologia, Hospital Unversitario Virgen Macarena, Avenida Dr Fedriani, 41071 Sevilla, Spain
  4. Hôpital Lariboisière, Paris, France
  1. E Tournier-Lasserve, INSERM U25, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75730 Paris Cedex 15. France, Telephone 0033 1 45 67 25 97; fax 0033 1 40 56 01 07; email: tournier{at}necker.fr

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Cerebral cavernous malformations are vascular malformations mostly located in the CNS. Their frequency is estimated close to 0.5% in the general population.1 Cerebral cavernous malformations occur as a sporadic or hereditary condition. From the Hispano-American population, familial forms were reported with a high frequency.2 CCM1, a hitherto unidentified gene mapping on chromosome 7 was shown to be involved in all families with cerebral cavernous malformations of Hispano-American descent with a strong founder effect.2 3 Around 50% of non-Hispano-American families showed linkage toCCM1 but no common haplotype was found.4 5 A recent study showed linkage of cerebral cavernous malformations to two additional loci.5 No Spanish family with cerebral cavernous malformations has been analysed so far.

(A) Pedigrees of the nine families with cerebral cavernous malformations. Black symbols=symptomatic patients with cavernous angiomas on MRI; half filled symbols=asymptomatic members with cavernous angiomas on MRI; empty symbols=asymptomatic members with normal MRI; question mark=members with unknown status. (B) Comparison of the Hispano-American CCM1 haplotype and the haplotypes segregating with the disease phenotype within Spanish families. Polymorphic markers are shown on the left. Numbers indicate the sizes in base pairs. Primers used to amplify D7S2409 were different from those in the Hispano-American families resulting in a different size of the amplified fragment. M65B was not studied in the Hispano-American families. Family CVE24 was not informative for D7S646. For families CVE17 and CVE29, the two haplotypes of the affected siblings are indicated. ND=not determined.

We report herein a genetic linkage analysis conducted on nine Spanish families with cerebral cavernous malformations. All procedures were approved by an ethics comittee. The families were unrelated and originated from different regions of Spain (south west (CVE2, 3, 4, 10, 17, 25), central (CVE24), south east (CVE28), and north east (CVE29). Seventy seven subjects including 55 potentially informative meioses and 12 spouses gave their informed consent. They were examined by a board certified neurologist, underwent cerebral MRI, and blood samples were taken. Magnetic resonance imaging was used to establish status for linkage analysis. Thirty four members had MRI diagnosis of cavernomas and were considered as affected. Among them, 14 experienced neurological symptoms (cerebral haemorrhage n=6, seizures n=8). Nineteen members with normal cerebral MRI were considered as healthy. Twelve members without MRI investigation had an unknown status. Analysis of pedigrees was consistent with an autosomal dominant pattern of inheritance (figure A).

Eight polymorphic microsatellite markers spanning theCCM1 interval were selected for linkage analysis. Four were chosen from the Généthon linkage map (D7S2410, D7S2409, D7S646, D7S689), and three from the Cooperative Human Linkage Center (D7S1813, D7S1789, D7S558). The last one (M65B) was identified by SL based on sequencing data of a bacterial artificial chromosome (Genbank HSAC000065; BAC RG085C05). The length of the genetic interval flanked by markers D7S2410 and D7S689 is 4 centimorgans (cM). Marker distances between D7S2410/D7S2409, D7S1813/D7S1789/D7S646/D7S558, and D7S689 have been estimated to be 2.2 cM, and 1.8 cM, respectively.3 Oligonucleotide sequences are available through the Genome Data Bank (John Hopkins University, Baltimore). Genotyping and linkage analysis (LINKAGE package version 5.1) were performed as previously described.5

Lod scores were calculated in the five families having a sufficient number of potentially informative meioses—that is, CVE3 (eight), CVE4 (16), CVE10 (seven), CVE25 (five), and CVE28 (seven). Lod scores higher than 1 were obtained for three families (CVE3, 4, and 28) for at least one marker. Due to incomplete informativity of three markers within family CVE4, lod scores did not reach the level of 3. In family CVE10, lod scores were close to 1 for four markers (D7S2410, D7S1789, D7S558, D7S689). Family CVE25 showed a lod score close to 0 for all markers. In this family, two affected and one asymptomatic sibling with normal standard MRI inherited the same haplotype from their affected father. When the data of all examined families were pooled, a maximum combined lod score of 5.92 was obtained for marker D7S2410 at θ=0.

In seven families (CVE2, 3, 4, 10, 24, 25, and 28), all affected members inherited an haplotype that was not shared by their healthy relatives (figure B). In family CVE17, both affected siblings inherited a distinct haplotype from their affected mother. Although the limited size of this family does not allow to formally conclude, this suggests genetic heterogeneity. In family CVE29, the two affected siblings inherited the same haplotypes from their mother and father whose status was unknown.

None of the families shared a common haplotype (figure B). In addition, the extended Hispano-American haplotype was not segregating with the disease phenotype in any of the nine families including the four families with suggested linkage toCCM1. However, two out of nine families (CVE2 and 3), the D7S646 (185bp) and D7S558 (107bp) alleles segregating with the disease phenotype were identical to the ones observed in the Hispano-American haplotype. Consequently, we analysed the frequency of this combination of alleles within a panel of 80 haplotypes of 40 healthy white subjects. Frequency was 17% compared with 22% in our Spanish sample. Therefore, this finding might be attributed to a random distribution of these alleles.

In conclusion, linkage analysis of Spanish families with cerebral cavernous malformations did not show any evidence for Hispano-American haplotype sharing or a founder effect. Although our sample was limited in size and does therefore not formally exclude the presence of the Hispano-American haplotype in additional Spanish families with cerebral cavernous malformations, this haplotype is most likely not predominant in Spain, and the strong founder effect seen in all published Hispano-American families with cerebral cavernous malformations might be specific for this population.

Acknowledgments

HJ is supported by the Schweizerische Stiftung für medizinisch-biologische Stipendien (Switzerland), SL by the Fonds de Recherche en Santé (Canada), PL by the Collège des Enseignants de Neurologie and ZENECA pharmaceutical group. The work was founded by INSERM, Ministère de l’Enseignement Superieur et de la Recherche, CSIC, and the Fondo de Investigacion de la Seguridad Social (Fiss: 99/0407).

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