cMyBP-C tidak terlalu diperlukan pada saat pembentukan sarkomer selama embryogenesis, tetapi

diperlukan untuk menjaga fungsi normal jantung. Ketiadaan cMyBP-C menyebabkan hipertrofi otot
jantung, peningkatan rasio berat jantung berat badan, pembesaran ventrikel, peningkatan
sensitivitas myofilament terhadap Ca2+ serta menurunkan fungsi diastolic dan systolic. Secara
histologis, ketiadaan Mybpc3 menyebabkan kekacauan kardiak miosit dan peningkatan
terbentuknya jaringan fibrosis.
cMyBP-C berfungsi sebagai rem pada mekanisme kontraksi otot jantung. Ketika fungsi ini
dihilangkan, kekuatan dan siklus kinetis meningkat. Berbanding lurus dengan peningkatan ini,
ketiadaan cMyBP-C menyebabkan waktu sistolik yang abnormal dengan pemendekan waktu
relaksasi dan peningkatan akselerasi yang dipaksakan pada serat otot. Kesimpulannya adalah
cMyBP-C dibutuhkan untuk menahan aktivitas berlebihan untuk mempertahankan fungsi ejeksi yang
normal. cMyBP-C mengatur posisi aktind an myosin dalam interaksi dan berperan sebagai
penghambat pergerakan

regulates the positioning of myosin and actin for interaction and acts as a tether to the
myosin S1 heads, limiting their mobility. This results in a decreased number of crossbridges formed,
which hinders force generation, due to its N-terminal C1-M-C2 region interacting with the myosin-S2
domain.[23][24][25][26] Furthermore, cMyBP-C contributes to the regulation of cardiac contraction at short
sarcomere length and is required for complete relaxation in diastole. [17][27]
Interactions of cMyBP-C with its binding partners vary with its posttranslational modification status.
At least three extensively characterized phosphorylation sites (Ser273, 282 and 302; numbering
refers to the mouse sequence) are localized in the M motif of cMyBP-C and are targeted by protein
kinases in a hierarchical order of events. In its dephosphorylated state, cMyBP-C binds
predominantly to myosin S2 and brakes crossbridge formation, however, when phosphorylated in
response to -adrenergic stimulation through activating cAMP-dependent protein kinase (PKA), it
favours binding to actin, then accelerating crossbridge formation, enhancing force development and
promoting relaxation.[28] Protein kinases identified thus far to phosphorylate cMyBP-C in the M motif
are PKA,[29][30][31][32][33] Ca2+/calmodulin-dependent kinase II (CaMKII),[34]ribosomal s6 kinase (RSK),

[35]

protein kinase D (PKD),[36][37] and protein kinase C (PKC).[32] Furthermore, GSK3 was described as

another protein kinase to phosphorylate cMyBP-C outside the M-domain in the proline-alanine-rich
actin-binding site at Ser133 in human myocardium (mouse Ser131).[38] Phosphorylation is required
for normal cardiac function and cMyBP-C stability,[39][40] and overall phosphorylation levels of cMyBP-C
are reduced in human and experimental heart failure.[41][42] Other posttranslational modifications of
cMyBP-C exist, which occur throughout the protein and are not thoroughly characterised yet, such
as acetylation,[43] citrullination,[44] S-glutathiolation,[45][46][47][48] S-nitrosylation[49] and carbonylation.[50]

Gen MyBPC3 berasal dari kromosom nomor 11p11.2. Gen ini merupakan gen keempat yang telah
diidentifikasi, yang dimana mutasinya diketahui telah menyebabkan terjaadinya kardiomiopati
hipertrofik. Mutasi pada gen ini merupakan mutasi terbanyak kedua dalam menyebabkan
kardiomiopati hipertrofik.
Mutasi pada gen ini menyebabkan pemotongan dari protein, shifts in reading frames, dan
terminasi kodon yang premature.Mutasi ini menyebabkan pemendekan protein serta lacking the
regulatory phosphorylatable M motif and/or major binding domains to other sarcomeric proteins.

Pathomechanisms
These data suggest haploinsufficiency as the main disease mechanism for heterozygous truncating
mutations.[77][78] A body of evidence exists that the mechanisms regulating the expression of mutant
allele involve the nonsense-mediated mRNA decay, the ubiquitin-proteasome system (UPS) and
the autophagy-lysosomal pathway after gene transfer of mutant MYBPC3 in cardiac myocytes or in
mice in vivo.[79][80][81][82][83][84] In contrast to truncating mutations, missense mutations lead, in most of the
cases (although difficult to specifically detect), to stable mutant cMyBP-Cs that are, at least in part,
incorporated into the sarcomere and could act as poison polypeptides on the structure and/or
function of the sarcomere. Homozygous or compound heterozygous mutations are therefore likely
subject to differential regulation depending on whether they are double missense, double truncating
or mixed missense/truncating mutations. The homozygous Mybpc3-targeted knock-in mice, which
genetically mimic the situation of severe neonatal cardiomyopathy are born without phenotype and
soon after birth develop systolic dysfunction followed by (compensatory) cardiac hypertrophy.[85]
[86]

The human c.772G>A transition results in low levels of three different mutant Mybpc3 mRNAs and

cMyBP-Cs in homozygous mice, suggesting a combination of haploinsufficiency and polypeptide

poisoning as disease mechanism in the homozygous state.[87] In addition, the combination of external
stress (such as neurohumoral stress or aging) and Mybpc3 mutations have been shown to impair
the UPS in mice,[88][89] and proteasomal activities were also depressed in patients with hypertrophic
cardiomyopathy or dilated cardiomyopathy.[90]
Skinned trabeculae or cardiac myocytes obtained from human patients carrying a MYBPC3 mutation
or from heterozygous and homozygous Mybpc3-targeted knock-in mice exhibited higher myofilament
Ca2+ sensitivity than controls.[91][92][93][94][95]Disease-modeling by engineered heart tissue (EHT)
technology with cardiac cells from heterozygous or homozygousMybpc3-targeted knock-in mice
reproduced observations made in human and mouse studies displaying abbreviated contractions,
greater sensitivity to external Ca2+ and smaller inotropic responses to various drugs (isoprenaline,
EMD 57033 and verapamil) compared to wild-type control EHTs.[96] Therefore, EHTs are suitable to
model the disease phenotype and recapitulate functional alterations found in mice with hypertrophic
cardiomyopathy. Another good system for modeling cardiomyopathies in the cell culture dish is the
derivation of cardiac myocytes from iPSC. Reports of human iPSC models of sarcomeric
cardiomyopathies showed cellular hypertrophy in most of the cases,[97][98][99][100] including one with the
c.2995_3010del MYBPC3 mutation that exhibited in addition to hypertrophy contractile variability in
the presence ofendothelin-1.[101]

Therapy[edit]
Because of their tissue selectivity and persistent expression recombinant adeno-associated
viruses (AAV) have therapeutic potential in the treatment of inherited cardiomyopathy resulting
from MYBPC3 mutations-[102] Several targeting approaches have been developed. [103][104] The most
recent is genome editing to correct a mutation by CRISPR/Cas9 technology.[105]Naturally existing as
part of the prokaryotic immune system, the CRISPR/Cas9 system has been used for correction of
mutations in the mammalian genome.[106] By inducing nicks in the double-stranded DNA and
providing a template DNA sequence, it is possible to repair mutations by homologous recombination.
This approach has not yet been evaluated forMYBPC3 mutations, but it could be used for each
single or clustered mutation, and therefore applied preferentially for frequent
founder MYBPC3 mutations.
Other strategies targeting the mutant pre-mRNA by exon skipping and/or spliceosome-mediated
RNA trans-splicing (SMaRT) have been evaluated for MYBPC3. Exon skipping can be achieved
using antisense oligonucleotide (AON) masking exonic splicing enhancer sequences and therefore
preventing binding of the splicing machinery and therefore resulting in exclusion of the exon from the
mRNA.[107][108] This approach can be applied when the resulting shorter, but in-frame translated protein
maintains its function. Proof-of-concept of exon skipping was recently shown in

homozygous Mybpc3-targeted knock-in mice.[85] Systemic administration of AAV-based AONs

to Mybpc3-targeted knock-in newborn mice prevented both systolic dysfunction and left ventricular
hypertrophy, at least for the duration of the investigated period. [85] For the human MYBPC3gene,
skipping of 6 single exons or 5 double exons with specific AONs would result in shortened in-frame
cMyBP-Cs, allowing the preservation of the functionally important phosphorylation and protein
interaction sites. With this approach, about half of missense or exonic/intronic truncating mutations
could be removed, including 35 mutations in exon 25. The other strategy targeting the mutant premRNA is SMaRT. Hereby, two independently transcribed molecules, the mutant pre-mRNA and the
therapeutic pre-trans-splicing molecule carrying the wild-type sequence are spliced together to give
rise to a repaired full-length mRNA.[109] Recently, the feasibility of this method was shown both in
isolated cardiac myocytes and in vivo in the heart of homozygous Mybpc3-targeted knock-in mice,
although the efficiency of the process was low and the amount of repaired protein was not sufficient
to prevent the development of the cardiac disease phenotype.[86] In principle, however, this SmART
strategy is superior to exon skipping or CRISPR/Cas9 genome editing and still attractive, because
only two pre-trans-splicing molecules, targeting the 5 and the 3 of MYBPC3 pre-mRNA would be
sufficient to bypass all MYBPC3mutations associated with cardiomyopathies and therefore repair the
mRNA.
AAV-mediated gene transfer of the full-length Mybpc3 (defined as gene replacement) dosedependently prevents the development of cardiac hypertrophy and dysfunction in
homozygous Mybpc3-targeted knock-in mice.[110] The dose-dependent expression of
exogenous Mybpc3 was associated with the down-regulation of endogenous mutant Mybpc3.
Additional expression of a sarcomeric protein is expected to replace partially or completely the
endogenous protein level in the sarcomere, as it has been shown in transgenic mice expressing
sarcomeric proteins