Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy
Jeanette Erdmann, PhD*,
J.örg Raible*,
Jaleh Maki-Abadi*,
Manfred Hummel,
Jan Hammann, MD*,
Bernd Wollnik, MD ,
Eckart Frantz, MD*,
Eckart Fleck, MD*,
Roland Hetzer, MD and
Vera Regitz-Zagrosek, MD*
* Departments of Internal Medicine and Cardiology, Charité, Campus Virchow-Klinikum, Humboldt University and Deutsches Herzzentrum, Berlin, Germany
Department of Medical Genetics, Child Health Institute, University of Istanbul, Istanbul, Turkey
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Figure 1 Diagram showing the domain structure of the myosin-binding protein C (MyBPC) polypeptide and the location of hypertrophic cardiomyopathy associated mutations identified in our patients.
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Figure 2 Electrophoresis of polymerase chain reaction (PCR) products after reverse transcriptase (RT)-PCR with primers located in exons 5/6 and 9 of the human MYBPC3 gene showing aberrant fragments resulting from the substitution of A for G at the splice donor site of exon 7 (IVS7+1G>A). The wild-type splice product is 233–base pair (bp) in length. Aberrant splice products resulting from the IVS7+1G>A mutation are either 184-bp (loss of exon 7) or 154-bp (loss of exons 7 and 8) in length. Lanes 1 and 2: RT-PCR products of patient 1331 carrying the IVS7+1G>A mutation; lane 3: negative control using water as a template; lanes 4 and 5: RT-PCR products of patient 1978 carrying the IVS7+1G>A mutation; lane 6: negative control using water as a template; lanes 7 and 8: RT-PCR products of control probands carrying only wild-type alleles. M = 100-bp ladder.
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Figure 3 Pedigrees of families with hypertrophic cardiomyopathy. Symbols denote gender and disease status: box = male; circle = female; darkened = full phenotype of hypertrophic cardiomyopathy; quarter = only discrete signs of the disease; clear = unaffected; slashed = deceased; SD = sudden death; + = genetically affected; - = genetically unaffected. (A) Pedigrees of index-patients (DNA 45, 70, 1893, and 1119) carrying missense mutations (R282W, G507R, C566R, V1115I) and pedigree of index-patient 7 carrying in-frame splicing mutation (IVS27+1G>A). (B) Pedigrees of index-patients (DNA 164, 6, 314, 8, 1206) carrying small deletions and insertions (delC390, insG791, insAA1042, delG1047, and insTTCA1231). (C) Pedigrees of index-patients (DNA 169, 1331, and 14) carrying splice mutations (IVS7+1G>A, IVS2-2A>G, IVS27+G>A) and pedigrees of index-patients (DNA 315 and 39) carrying nonsense mutations (Q1233X).
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Figure 4 Haplotypes across the myosin-binding protein C gene (MYBPC3) locus associated with the IVS7+1G>A mutation are shown. The disease-associated haplotypes of the family members of patients 1331 and 169 are boxed. The marker loci used for haplotype construction, covering a distance of  0.6 cM, are indicated at the left, in telomeric-centromeric order, from top to bottom.
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