Molekulargenetische Diagnostik
Praxis Dr. Mato Nagel

Membran-Cofaktor-Protein

Das Membranprotein, welches vom MCP-Gen kodiert wird, besitzt eine wichtige Funktion in der Complement-Kaskade und stellt den zellulären Rezeptor des Masernvirus. Heterozygote Mutationen können ein atypisches (hereditäres) hämolytisch urämisches Syndrom (aHUS) auslösen. Theoretisch ist auch eine Beeinflussung der Infektanfälligkeit gegenüber Masern denkbar.

Proteinstruktur

Das der Membranrezeptor passiert die Basalmembran nur einmalig. Das kurze N-terminale Ende befindet sich intrazellulär. Extrazellulär unterscheiden wir vom C-terminalen Ende ausgehend 4 SCR-(short consensus repeat)-Domainen und anschließend zwei serin-, threonin- und prolin-reiche Domainen, STR.

Expression

Der Rezeptor for das Complementsystem (CD46) wird auf allen Zellen außer Erythrozyten gefunden.

Interpretation

Heterozygote Mutationen können entweder zu einer verminderten Anzahl von Rezeptoren auf der Zelloberfläche führen. Dies ist bei etwa 75% der Mutationen der Fall. Die übrigen Mutationen zeigen zwar eine normale oder eher erhöhte Membranexpression, aber eine verminderte Funktion. 93% der Mutationen finden sich in einer der 4 extrazellulären SCR-(short consensus repeat)-Domainen, die für die Regulation der Complementfunktion verantwortlich sind.

Die Penetranz der heterozygoten MCP-Mutationen für das atypische HUS beträgt wird mit 54% angegeben.[1]

Diagnostik:

Clinic Untersuchungsmethoden Familienuntersuchung
Bearbeitungszeit 5
Probentyp genomic DNA
Clinic Untersuchungsmethoden Multiplex ligationsabhängige Amplifikation
Bearbeitungszeit 20
Probentyp genomic DNA
Clinic Untersuchungsmethoden Direkte Sequenzierung der proteinkodierenden Bereiche eines Gens
Bearbeitungszeit 20
Probentyp genomic DNA
Clinic Untersuchungsmethoden Hochdurchsatz-Sequenzierung
Bearbeitungszeit 25
Probentyp genomic DNA

Krankheiten:

Hämolytisch Urämisches Syndrom
ADAMTS13
C3
C4BPA
C4BPB
CD46
CFB
CFH
CFHR1
CFHR2
CFHR3
CFHR4
CFHR5
CFI
CLU
DGKE
Methylmalonazidurie
Methylmalonazidurie Typ mut
MUT
Methylmalonazidurie mit Homozysteinurie cblC
MMACHC
Methylmalonazidurie mit Homozysteinurie cblD
MMADHC
PIGA
THBD
Masern-Infektanfälligkeit
CD46
Meningokokken-Infektanfälligkeit
C3
C5
C7
C8A
C8B
C8G
C9
CD46
CFB
CFD
CFH
CFP

Referenzen:

1.

Xiang L et al. (1999) Quantitative alleles of CR1: coding sequence analysis and comparison of haplotypes in two ethnic groups.

[^]
2.

Nürnberger J et al. (2009) Eculizumab for atypical hemolytic-uremic syndrome.

[^]
3.

Santoro F et al. (1999) CD46 is a cellular receptor for human herpesvirus 6.

[^]
4.

Tatsuo H et al. (2000) SLAM (CDw150) is a cellular receptor for measles virus.

[^]
5.

Källström H et al. (2001) Attachment of Neisseria gonorrhoeae to the cellular pilus receptor CD46: identification of domains important for bacterial adherence.

[^]
6.

Marie JC et al. (2002) Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell induced inflammation.

[^]
7.

Kemper C et al. (2003) Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype.

[^]
8.

Schneider-Schaulies J et al. (2003) Measles infection of the central nervous system.

[^]
9.

Johansson L et al. (2003) CD46 in meningococcal disease.

[^]
10.

Richards A et al. (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.

[^]
11.

Gaggar A et al. (2003) CD46 is a cellular receptor for group B adenoviruses.

[^]
12.

Noris M et al. (2003) Familial haemolytic uraemic syndrome and an MCP mutation.

[^]
13.

Goodship TH et al. (2004) Mutations in CD46, a complement regulatory protein, predispose to atypical HUS.

[^]
14.

Esparza-Gordillo J et al. (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32.

[^]
15.

Fremeaux-Bacchi V et al. (2005) The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts.

[^]
16.

Gaggar A et al. (2005) Localization of regions in CD46 that interact with adenovirus.

[^]
17.

Cassiani-Ingoni R et al. (2005) CD46 on glial cells can function as a receptor for viral glycoprotein-mediated cell-cell fusion.

[^]
18.

Yanagi Y et al. (2006) Measles virus receptors and tropism.

[^]
19.

Tishon A et al. (2006) CD4 T cell control primary measles virus infection of the CNS: regulation is dependent on combined activity with either CD8 T cells or with B cells: CD4, CD8 or B cells alone are ineffective.

[^]
20.

Sood R et al. (2006) Gene expression patterns in human placenta.

[^]
21.

Caprioli J et al. (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.

[^]
22.

Richards A et al. (2007) Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome.

[^]
23.

Yanagi Y et al. (2006) Measles virus: cellular receptors, tropism and pathogenesis.

[^]
24.

Post TW et al. (1991) Membrane cofactor protein of the complement system: alternative splicing of serine/threonine/proline-rich exons and cytoplasmic tails produces multiple isoforms that correlate with protein phenotype.

[^]
25.

Oliaro J et al. (2006) Ligation of the cell surface receptor, CD46, alters T cell polarity and response to antigen presentation.

[^]
26.

Zheng XL et al. (2008) Pathogenesis of thrombotic microangiopathies.

[^]
27.

Karosi T et al. (2008) Disease-associated novel CD46 splicing variants and pathologic bone remodeling in otosclerosis.

[^]
28.

Yanagi Y et al. (2009) Measles virus receptors.

[^]
29.

Kemper C et al. (2009) Measles virus and CD46.

[^]
30.

Purcell DF et al. (1991) Identification of four different CD46 (MCP) molecules with anti-peptide antibodies.

[^]
31.

Santiago C et al. (2010) Structure of the measles virus hemagglutinin bound to the CD46 receptor.

[^]
32.

Haralambieva IH et al. (2011) Genetic polymorphisms in host antiviral genes: associations with humoral and cellular immunity to measles vaccine.

[^]
33.

Ovsyannikova IG et al. (2011) The association of CD46, SLAM and CD209 cellular receptor gene SNPs with variations in measles vaccine-induced immune responses: a replication study and examination of novel polymorphisms.

[^]
34.

Andrews PW et al. (1985) A human cell-surface antigen defined by a monoclonal antibody and controlled by a gene on human chromosome 1.

[^]
35.

Bora NS et al. (1989) Structural gene for human membrane cofactor protein (MCP) of complement maps to within 100 kb of the 3' end of the C3b/C4b receptor gene.

[^]
36.

Lublin DM et al. (1988) Molecular cloning and chromosomal localization of human membrane cofactor protein (MCP). Evidence for inclusion in the multigene family of complement-regulatory proteins.

[^]
37.

Pirson Y et al. (1987) Hemolytic uremic syndrome in three adult siblings: a familial study and evolution.

[^]
38.

McIntyre JA et al. (1983) Human trophoblast-lymphocyte cross-reactive (TLX) antigens define a new alloantigen system.

[^]
39.

Cui W et al. (1993) Characterization of the promoter region of the membrane cofactor protein (CD46) gene of the human complement system and comparison to a membrane cofactor protein-like genetic element.

[^]
40.

Dörig RE et al. (1993) The human CD46 molecule is a receptor for measles virus (Edmonston strain).

[^]
41.

Källström H et al. (1997) Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic Neisseria.

[^]
42.

Warwicker P et al. (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome.

[^]

 

 
Ihre Nachricht: