Published Online
on March 3, 2003

A more recent version of this article appeared on March 18, 2003

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Submitted on January 31, 2002
Revised on November 20, 2002
Accepted on December 10, 2002

Mutations in the Human Muscle LIM Protein Gene in Families With Hypertrophic Cardiomyopathy

Christian Geier MD, Andreas Perrot MSc, Cemil Özcelik MD, Priska Binner PhD, Damian Counsell MSc, Katrin Hoffmann MD, Bernhard Pilz MD, Yvonne Martiniak MSc, Katja Gehmlich BSc, Peter F.M. van der Ven PhD, Dieter O. Fürst PhD, Arnold Vornwald MD, Eberhard von Hodenberg MD, Peter Nürnberg PhD, Thomas Scheffold MD, Rainer Dietz MD, and Karl Josef Osterziel MD^*

From the Universitätsklinikum Charité/Kardiologie am Campus Buch und Virchow Klinikum (C.G., A.P., C.O., K.H., B.P., Y.M., R.D., K.J.O.), Humboldt-Universität zu Berlin, Berlin, Germany; Max-Delbrück-Centrum für Molekulare Medizin (C.G., K.H., P.N.), Berlin-Buch, Germany; Institut für Molekulare und klinische Herz-Kreislaufforschung-Bereich Molekulargenetik (P.B., T.S.), Universität Witten-Herdecke, Germany; MRC Human Genome Mapping Project Resource Centre (D.C.), Hinxton, Cambridge, UK; Abteilung Zellbiologie, Institut für Biochemie und Biologie, Universität Potsdam (K.G., P.F.M.v.d.V., D.O.F.), Potsdam, Germany; DRK-Blutspendedienst Berlin (A.V.), Berlin, Germany; Herzzentrum Lahr/Baden (E.v.H.), Baden, Germany; and Universitätsklinikum Charité, Institut für Medizinische Genetik, Humboldt-Universität (P.N.), Berlin, Germany.

^* To whom correspondence should be addressed. E-mail: karljosef.osterziel{at}charite.de.

Background--Muscle LIM protein (MLP) is an essential nuclear regulator of myogenic differentiation. Additionally, it may act as an integrator of protein assembly of the actin-based cytoskeleton. MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans.

Methods and Results--We analyzed 1100 unrelated individuals (400 patients with DCM, 200 patients with HCM, and 500 controls) for mutations in the human CRP3 gene that encodes MLP. We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls. All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with -actinin and with certain muscle-specific transcription factors. Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to -actinin. All 3 index patients were characterized by typical asymmetrical septal hypertrophy. Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP.

Conclusion--Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM.

Key words: cardiomyopathy • genes • hypertrophy

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