Prenons un exemple concret, l'origine de la maladie LAD-III (Leukocytes adhésion deficiency-III)
Tout d'abord un petit rappel :
-Les leucocytes (globules blancs) sont importants pour prévenir et guérir les infections. Pour être fonctionnels ils nécessitent (entre autre) les intégrines béta 1 et 2
-Les plaquettes sont importantes pour prévenir et guérir les saignements. Pour être fonctionelles elles nécessitent (entre autre) les intégrines béta 3 et alpha 2
-LAD-I, les malades ont un troubles de leucocytes et sont sujets à un nombre très élevé d'infections. Cause : mutation des integrines béta 2
-Thrombastenie de Glanzmann, les malades ont un trouble des plaquette et sont sujets à un nombre très élevé d'hémottagies. Cause : mutation des intégrines alpha 2 et béta 3
-LAD-III=patients avec les symptômes de LAD-1 et de la thrombastenie de Glanzmann.
Cause : pour l'instant pas très clair, surtout qu'il n'y a pas de mutations dans leurs intégrines.
Ce petit rappel terminé, vous comprendrez surement mieux pourquoi il est intéressant de découvrire l'origine de la maladie LAD-III.
Certes. Mais pourquoi en faire une news pour ActuSF ?
Ben parce vient de sortir dans Nature medicine, non pas un, mais TROIS papiers simultanés, de trois groupes différents, décortiquant l'origine de cette maladie. En l'occurence une mutation dans KINDLIN3.
Dans le milieu scientifique c'est un évenement rarrissime.
Croyez-moi, c'est beau.
Et je ne voudrai pas être à la place de l'équipe ayant publié dans J. Ex. Med en 2007 que LAD-III était probablement associée à une autre mutation (dans CALDAGGEF1) ...
Nat Med. 2009 Feb 22.
Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation.
Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M,
Tomlinson I, Hogg N.
Integrins are the major adhesion receptors of leukocytes and platelets. beta(1) and
beta(2) integrin function on leukocytes is crucial for a successful immune response and
the platelet integrin alpha(IIb)beta(3) initiates the process of blood clotting through
binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but
become active after 'inside-out' signaling through other membrane receptors. Subjects
with leukocyte adhesion deficiency-1 (LAD-I) do not express beta(2) integrins because of
mutations in the gene specifying the beta(2) subunit, and they suffer recurrent bacterial
infections. Mutations affecting alpha(IIb)beta(3) integrin cause the bleeding disorder
termed Glanzmann's thrombasthenia. Subjects with LAD-III show symptoms of both LAD-I and
Glanzmann's thrombasthenia. Their hematopoietically-derived cells express beta(1),
beta(2) and beta(3) integrins, but defective inside-out signaling causes immune
deficiency and bleeding problems. The LAD-III lesion has been attributed to a C --> A
mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange
factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein, but we
show that this change is not responsible for the LAD-III disorder. Instead, we identify
mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein
as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result
in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably,
transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not
CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and
migration.
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Nat Med. 2009 Feb 22.
Kindlin-3 is required for beta(2) integrin-mediated leukocyte adhesion to endothelial
cells.
Moser M, Bauer M, Schmid S, Ruppert R, Schmidt S, Sixt M, Wang HV, Sperandio M, Fässler R.
Integrin activation is essential for the function of all blood cells, including platelets
and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the
activation of the beta(1) and beta(3) integrins on platelets. Impaired activation of
beta(1), beta(2) and beta(3) integrins on platelets and leukocytes is the hallmark of a
rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III,
characterized by severe bleeding and impaired adhesion of leukocytes to inflamed
endothelia. Here we show that Kindlin-3 also binds the beta(2) integrin cytoplasmic
domain and is essential for neutrophil binding and spreading on beta(2)
integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement
C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm
adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo,
whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to
activate the beta(1), beta(2) and beta(3) integrin classes, and loss of Kindlin-3
function is sufficient to cause a LAD-III-like phenotype in mice.
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Nat Med. 2009 Feb 22.
A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans.
Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV.
Monogenic deficiency diseases provide unique opportunities to define the contributions of
individual molecules to human physiology and to identify pathologies arising from their
dysfunction. Here we describe a deficiency disease in two human siblings that presented
with severe bleeding, frequent infections and osteopetrosis at an early age. These
symptoms are consistent with but more severe than those reported for people with
leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from
an inability to activate the integrins expressed on hematopoietic cells, including
platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two
individuals showed integrin activation defects. Several proteins previously implicated in
integrin activation, including Ras-associated protein-1 (RAP1) and calcium and
diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1), were present
and functional in these cell lines. The genetic basis for this disease was traced to a
point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene.
When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins
became responsive to activation signals. These results identify a genetic disease that
severely compromises the health of the affected individuals and establish an essential
role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneic bone marrow
transplantation was shown to alleviate the symptoms of the disease.
