Dilated Cardiomyopathy 1Y (CMD1Y / TPM1-Related Dilated Cardiomyopathy): Comprehensive Research Report

1. Disease Information

Overview. Dilated Cardiomyopathy 1Y (CMD1Y) is a monogenic, autosomal dominant subtype of primary/familial dilated cardiomyopathy (DCM) caused by heterozygous missense mutations in TPM1 (alpha-tropomyosin, tropomyosin-1), the gene encoding the major sarcomeric thin-filament protein that co-regulates calcium-dependent actin–myosin interaction with the troponin complex. The disease is characterized by left ventricular (and often biventricular) dilation with impaired systolic contractile function, leading to progressive congestive heart failure; some reported patients died in the third to sixth decades of life OMIM #611878. Ultrastructurally, electron microscopy of affected myocardium shows abnormal sarcomere structure OMIM #611878.

Key identifiers: - OMIM (phenotype): #611878 — CARDIOMYOPATHY, DILATED, 1Y; CMD1Y - OMIM (gene): 191010 — TROPOMYOSIN 1; TPM1 - HGNC: 12010 (TPM1) — thegencc.org/genes/HGNC:12010 - UniProt: P09493 (tropomyosin alpha-1 chain) - Locus: 15q22.1–q22.2 - MedGen: C2678476 — MedGen C2678476 / NIH GTR - Orphanet (broader entity): ORPHA:154 — Familial isolated dilated cardiomyopathy - Related MONDO/parent concept: primary/idiopathic dilated cardiomyopathy, MONDO:0005021 - Allelic disorders at the same TPM1 locus:* Familial Hypertrophic Cardiomyopathy 3 (HCM3), Left Ventricular Noncompaction 9 (LVNC9), and CMD1E (an earlier-numbered TPM1-linked DCM designation, illustrating that TPM1 maps to more than one historical CMD1x sub-label)

Synonyms/alternative names: Cardiomyopathy, dilated, 1Y; CMD1Y; TPM1-related dilated cardiomyopathy; alpha-tropomyosin cardiomyopathy; DCM type 1Y (DCM1Y).

Evidence basis: This entry is derived almost entirely from aggregated case-level and small-pedigree reports (individual families and probands identified through linkage analysis, targeted Sanger sequencing, or next-generation sequencing panels) rather than large disease registries — reflecting the rarity of TPM1-DCM as a cause of DCM overall. Functional/mechanistic characterization comes from in vitro biochemical, biophysical, and iPSC-cardiomyocyte/computational studies of specific variants.

2. Etiology

Disease-causal factor. CMD1Y is caused by heterozygous missense mutations in TPM1 on chromosome 15q22.1, inherited in an autosomal dominant pattern OMIM #611878. Approximately 30 distinct TPM1 variants have been reported in association with DCM1Y to date (per aggregated literature review) PMC8758022.

Genetic risk factors: - Causal missense variants cluster across the coiled-coil tropomyosin rod domain and disrupt either (a) surface charge distribution affecting actin binding, or (b) allosteric communication with the troponin complex. - Documented pathogenic/likely pathogenic DCM-causing TPM1 variants include: - E40K and E54K — the founding CMD1Y mutations, identified by Olson et al. via linkage analysis of two DCM pedigrees; described as altering the surface charge of alpha-tropomyosin (PMID: 11273725, J Mol Cell Cardiol, 2001). - D230N (Asp230Asn) — identified in two Caucasian probands and segregating with disease in 14 affected relatives; structural basis characterized by X-ray/biophysical study (PMID: 28600229); ClinVar RCV000036354. - M8R (Met8Arg) — DCM/LVNC-associated variant with in silico and in vitro modeling of hypocontractility mechanism (PMC11392859); ClinVar RCV000036318. - K30E (Lys30Glu) — de novo variant causing severe pediatric DCM with LV noncompaction; destabilizes the N-terminal tropomyosin domain (PMID: 39684770, 2024). - E114Q — novel missense variant (c.340G>C) identified in a Chinese Han family, segregating with maternal death from DCM at age 50 (PMID: 35029218, 2022). - T237S — reported as likely pathogenic in a DCM proband. - E62Q is the classic HCM-causing (not DCM) TPM1 variant, useful as a mechanistic contrast (see Section 6). - Allele frequency: DCM-causing TPM1 variants are absent or present at extremely low frequency in population reference databases (gnomAD), consistent with pathogenicity and highly penetrant dominant disease; TPM1 as a whole gene shows constraint against missense variation in its functional (coiled-coil) domains. - Modifier genes: No validated CMD1Y-specific modifier genes are established; general DCM modifier/second-hit loci (e.g., titin truncating variants) may exacerbate phenotype in digenic contexts, as recognized broadly in the DCM genetics literature (PMC4288017, "Genetic Causes of Dilated Cardiomyopathy").

Environmental/other risk factors: No disease-specific environmental triggers are established for CMD1Y; as with other genetic DCM, generic stressors that unmask or accelerate cardiomyopathy (pregnancy, alcohol, cardiotoxic chemotherapy, viral myocarditis, tachyarrhythmia) may in principle act as second hits, but this has not been specifically documented for TPM1 carriers in the literature reviewed.

Protective factors: None specifically documented for TPM1/CMD1Y.

Gene–environment interactions: Not specifically characterized for this subtype in the literature surveyed.

3. Phenotypes

Because DCM1Y is a form of DCM, its phenotype overlaps substantially with nonsyndromic/idiopathic DCM, with variable severity and age of onset reported across pedigrees — from neonatal-onset lethal disease (K30E case, onset at 2 weeks of life) to adult-onset disease with death in the third–sixth decades OMIM #611878.

Onset/severity/progression: Highly variable — reported onset spans neonatal to adult; disease course is generally progressive, with several reported deaths from heart failure ranging from early childhood (age 3 years 8 months, K30E) to middle adulthood (ages 27–50 across different variant carriers). Severity correlates loosely with the degree of hypocontractility produced by the specific variant (see Section 6).

Frequency among affected individuals: Given the small numbers of reported families (case reports/small pedigrees), formal phenotype-frequency statistics (percentage penetrance for each sub-phenotype) are not established; qualitative HPO frequency terms (e.g., "typical" for cardiac dilation, "occasional" for LV noncompaction overlap) would be more appropriate than numeric percentages.

Quality of life impact: Not separately quantified for CMD1Y specifically; as with general heart-failure populations, expect substantial QoL burden proportional to NYHA functional class, captured generically via tools like the Kansas City Cardiomyopathy Questionnaire (KCCQ) in broader DCM literature — no disease-specific QoL study identified for this subtype.

4. Genetic/Molecular Information

Causal gene: TPM1 (Tropomyosin 1, alpha), OMIM *191010, HGNC:12010, UniProt P09493, located at 15q22.1–q22.2, encoding the major cardiac/striated-muscle tropomyosin isoform (a ~284-amino-acid, highly alpha-helical coiled-coil protein that polymerizes head-to-tail along the actin thin filament).

Variant classification and type: All reported CMD1Y-causing variants to date are heterozygous missense mutations (no frameshift/nonsense/splice-site DCM1Y variants identified in the literature reviewed), consistent with a dominant-negative or altered-function mechanism rather than simple haploinsufficiency. Representative variants and their ClinVar classifications: - p.Asp230Asn (c.688G>A) — classified pathogenic for "Primary dilated cardiomyopathy" (ClinVar RCV000036354) - p.Met8Arg (c.23T>G) — ClinVar RCV000036318 - p.Glu40Lys, p.Glu54Lys — originally described by Olson et al. 2001 (PMID: 11273725) - p.Lys30Glu (c.88A>G) — de novo, functionally characterized 2024 (PMID: 39684770) - p.Glu114Gln (c.340G>C) — novel, 2022 Chinese pedigree (PMID: 35029218)

Population frequency: DCM-causing TPM1 missense variants are essentially absent from gnomAD/population databases, consistent with rarity and pathogenicity; TPM1 as a gene shows regional missense constraint concentrated in actin-binding and troponin-interacting surfaces of the coiled-coil.

Somatic vs. germline: All reported CMD1Y variants are germline; most are familial (autosomal dominant transmission with variable expressivity), though de novo occurrence has been documented (K30E case, PMID: 39684770).

Functional consequences — mechanism divides HCM vs. DCM at the same locus. A key mechanistic insight, established by direct comparison of an HCM-causing (E62Q) and a DCM-causing (E54K) TPM1 variant using iPSC-derived cardiomyocytes and computational modeling (PMID: 39436707, J Clin Invest, 2024): - DCM variant E54K: decreases calcium sensitivity and produces hypocontractility — via long-range allosteric effects that increase the association rate of the C-terminal troponin I mobile domain, yielding shorter-lived twitches, impaired length-dependent activation, and ~3-fold decreased peak force. Net effect: increased tissue compliance, chamber dilation without hypertrophy. - HCM variant E62Q (contrast case): increases calcium sensitivity, reduces tropomyosin molecular stiffness, favors the "closed" (activating) regulatory state, and produces hypercontractility (>3-fold increased peak force), driving hypertrophy. - This supports a unifying framework in which intrinsically decreased actomyosin contractility from TPM1 variants produces cardiomyocyte lengthening/dilation (DCM), while intrinsically increased contractility produces hypertrophy (HCM) — despite both classes of mutation affecting the same protein.

For the K30E variant specifically: differential scanning calorimetry showed decreased thermal/calorimetric stability of tropomyosin domains 2–3 and reduced thermal stability of the tropomyosin–actin complex; in vitro motility assays showed ~37% reduction in thin-filament sliding velocity across physiological calcium concentrations, with increased calcium sensitivity (pCa50 5.97 vs 5.83 WT) but impaired maximal force — indicating a complex, domain-destabilizing hypocontractile mechanism (PMID: 39684770).

For D230N: structural studies indicate the mutation perturbs local coiled-coil geometry, altering tropomyosin's positional regulation on the thin filament (PMID: 28600229).

Modifier genes / epigenetics / chromosomal abnormalities: None specifically reported for CMD1Y; not applicable as this is a single-gene missense disorder without described epigenetic modulation or chromosomal rearrangement mechanism in the literature surveyed.

Gene Ontology / pathway suggestions: - GO:0003779 — actin binding - GO:0005523 — tropomyosin binding - GO:0060048 — cardiac muscle contraction - GO:0086003 — cardiac muscle cell contraction - GO:0055010 — ventricular cardiac muscle tissue morphogenesis - GO Cellular Component: GO:0030017 — sarcomere; GO:0036379 — myofilament; GO:0005865 — striated muscle thin filament

5. Environmental Information

No disease-specific environmental, infectious, or occupational/toxin exposures are documented as causal for CMD1Y in the literature surveyed — it is a purely monogenic sarcomeric cardiomyopathy. As is generic to DCM broadly, comorbid exposures (alcohol, cardiotoxic chemotherapeutics, viral myocarditis) could theoretically modify phenotype expression/severity in a genetically susceptible carrier, but no CMD1Y-specific gene–environment study was identified.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream): 1. Molecular trigger: Heterozygous TPM1 missense mutation alters the tropomyosin coiled-coil structure (surface charge, domain stability, or troponin-interaction interface). 2. Thin-filament regulatory defect: Mutant tropomyosin shows reduced calcium sensitivity and/or destabilized interaction with actin and the troponin complex, shifting the tropomyosin-actin regulatory equilibrium and altering cross-bridge cycling kinetics. 3. Cellular contractile defect: Reduced peak isometric force generation and impaired length-dependent activation in cardiomyocytes (demonstrated directly via in vitro motility assays and iPSC-CM/engineered heart tissue force measurements) — net hypocontractility. 4. Tissue/organ remodeling: Chronic hypocontractility drives compensatory cardiomyocyte lengthening (sarcomere addition in series rather than parallel, as in hypertrophy), increased ventricular compliance, and progressive chamber dilation without wall thickening. 5. Organism-level manifestation: Reduced systolic function → reduced cardiac output → neurohormonal activation (renin-angiotensin-aldosterone, sympathetic) → progressive congestive heart failure, arrhythmia risk, and in severe/pediatric-onset cases, rapid decompensation and death.

Molecular pathways: Sarcomeric thin-filament calcium-regulated contraction (troponin–tropomyosin–actin regulatory unit); secondary activation of cardiac stress/remodeling pathways typical of heart failure (natriuretic peptide signaling, RAAS, sympathetic/adrenergic signaling) as downstream consequences rather than primary drivers.

Cellular processes: Altered actomyosin cross-bridge cycling; impaired calcium-dependent activation of the thin filament; cardiomyocyte structural remodeling (elongation).

Protein dysfunction: Structural destabilization of the tropomyosin coiled-coil (loss of thermal/calorimetric stability in specific domains, e.g., K30E; altered coiled-coil geometry, e.g., D230N; altered surface charge affecting actin-binding affinity, e.g., E40K/E54K).

Biochemical/functional abnormalities: Decreased calcium sensitivity of force generation in some variants; reduced maximal force and reduced thin-filament sliding velocity in in vitro motility assays; altered troponin I C-terminal mobile-domain dynamics (E54K, allosteric mechanism).

Suggested ontology terms: - GO (biological process): GO:0060048 (cardiac muscle contraction), GO:0086001 (cardiac muscle cell action potential), GO:0055010 (ventricular cardiac muscle tissue morphogenesis), GO:0003009 (skeletal/cardiac muscle contraction - regulation of muscle contraction: GO:0006937) - GO (molecular function): GO:0003785 (actin monomer binding), GO:0005523 (tropomyosin binding) - CL (cell type): CL:0000746 (cardiac muscle cell); CL:0002098 (ventricular cardiac myocyte) - UBERON: UBERON:0002082 (cardiac ventricle); UBERON:0002080 (heart left ventricle)

Molecular profiling / advanced technologies: The most recent mechanistic dissection (PMID: 39436707, 2024) used human iPSC-derived cardiomyocytes, engineered heart tissue force measurements, and computational (myofilament) modeling to directly compare HCM (E62Q) vs. DCM (E54K) TPM1 variants — representative of state-of-the-art functional genomics approaches for sarcomeric cardiomyopathy variant interpretation. No transcriptomic/proteomic/single-cell dataset specific to CMD1Y myocardium was identified in this search.

7. Anatomical Structures Affected

• Organ level: Heart (primary); specifically left ventricle (dilation, reduced EF) and frequently right ventricle/biventricular involvement; secondary systemic effects of heart failure (pulmonary congestion, hepatic congestion, renal hypoperfusion) as downstream complications. Body system: cardiovascular.
• Tissue/cell level: Cardiac (striated) muscle tissue; ventricular cardiomyocytes (CL:0002098) are the principal affected cell population.
• Subcellular level: Sarcomere/myofilament (GO:0030017 sarcomere; GO:0036379 myofilament) — specifically the thin filament (actin–tropomyosin–troponin complex).
• Localization: Diffuse myocardial involvement (not focal); in the LVNC9-overlap phenotype, additional apex/mid-ventricular noncompaction of the left ventricular wall is described, sometimes with Ebstein anomaly of the tricuspid valve or mitral insufficiency in the allelic condition OMIM #611878.
• UBERON terms: UBERON:0002079 (left cardiac ventricle), UBERON:0002080/UBERON:0002082 (cardiac ventricle), UBERON:0006566 (cardiac muscle tissue).

8. Temporal Development

• Onset: Highly variable — documented range from neonatal (2 weeks of life, K30E case, PMID 39684770) to adult onset (40s, E114Q case, PMID 35029218); OMIM describes death "in the third to sixth decades of life in some patients," implying typical adult-onset presentation is common but pediatric/severe presentations occur with specific variants.
• Progression: Generally progressive — chamber dilation and systolic dysfunction worsen over time; some patients decompensate despite guideline-directed medical therapy (e.g., the K30E infant died of progressive heart failure at 3 years 8 months despite treatment).
• Disease course pattern: Chronic, progressive heart failure course typical of sarcomeric DCM, punctuated by risk of malignant arrhythmia/sudden death.
• Critical periods: Neonatal/early-childhood presentation (as with de novo K30E) appears to portend a particularly aggressive, rapidly fatal course, suggesting these patients represent a high-risk subgroup warranting early transplant evaluation.

9. Inheritance and Population

• Inheritance pattern: Autosomal dominant OMIM #611878.
• Penetrance/expressivity: Variable expressivity is evident from the literature — the same gene (and even overlapping variant positions) can produce DCM, LVNC, or HCM phenotypes depending on the specific substitution and its biophysical effect on tropomyosin (see Section 6); within-family phenotypic variability is also described (e.g., D230N segregating across 14 affected relatives with presumably variable severity).
• De novo occurrence: Documented (K30E, PMID 39684770), alongside clearly familial transmission (D230N in two large multigenerational families; E114Q in a Chinese Han pedigree with maternal death from DCM).
• Genetic anticipation, germline mosaicism, founder effects, consanguinity: Not specifically documented for CMD1Y in the literature surveyed.
• Epidemiology (broader DCM context, since CMD1Y-specific incidence/prevalence figures are not separately tabulated):
• Overall DCM prevalence has historically been estimated at ~1:2,500, with more recent population-genomic reappraisals suggesting a substantially higher effective prevalence, potentially ≥1 in 250 individuals when including subclinical/genotype-positive cases (NCBI Bookshelf NBK553847).
• Familial DCM accounts for roughly 20–50% of cases depending on screening rigor (historically underestimated at ~7%, revised upward to 30–60% of index cases with systematic family echocardiographic screening) (JACC: Heart Failure 2022).
• Up to 40 genes are implicated in genetic DCM overall, of which TPM1 is a well-established but relatively rare cause (encoding the thin-filament, not the more commonly implicated genes TTN, LMNA, MYH7, or BAG3) (PMC4288017).
• TPM1-specific prevalence among genotyped DCM cohorts is low (a minority contributor relative to titin-truncating variants, which are the single largest genetic cause of DCM); exact percentage contribution of TPM1 to genetic DCM was not precisely quantified in the sources reviewed here and would benefit from a dedicated cohort-frequency search if needed for curation.
• Population demographics: No specific ethnic/geographic enrichment documented for TPM1-DCM; reported pedigrees span Caucasian (D230N families), Chinese Han (E114Q family), and other ancestries, consistent with a pan-ethnic distribution typical of private/rare sarcomeric variants rather than a founder mutation.
• Sex ratio / age distribution: Not specifically reported for CMD1Y; general DCM has a male predominance in adult-onset disease, though pediatric/de novo cases (as in K30E) affected a female proband.

10. Diagnostics

• Clinical/imaging tests:
• Echocardiography — primary diagnostic modality; demonstrates LV (± RV) dilation, reduced ejection fraction/fractional shortening, and can detect associated LV noncompaction.
• Cardiac MRI — for tissue characterization, fibrosis assessment (late gadolinium enhancement), and confirmation of noncompaction where suspected.
• Electrocardiography — sinus tachycardia, conduction abnormalities, and arrhythmia surveillance.
• Electron microscopy of myocardial biopsy — historically used to show abnormal sarcomere ultrastructure in early OMIM-cataloged cases, though endomyocardial biopsy is not standard first-line diagnostic practice today.
• Biomarkers: Standard heart-failure biomarkers (BNP/NT-proBNP) apply generically; no CMD1Y-specific biomarker identified.
• Genetic testing:
• Clinical DCM gene panels commonly include TPM1 among ~40–100+ genes tested (panels of up to ~78 genes for hereditary DCM are commercially available).
• Confirmatory approach in reported cases: next-generation sequencing (whole-exome or targeted panel) followed by Sanger sequencing confirmation and familial segregation analysis (as used for E114Q, PMID 35029218, and K30E, PMID 39684770).
• Cascade/family genetic testing is recommended once a proband's causal variant is identified, given the autosomal dominant pattern.
• Clinical criteria: Standard DCM diagnostic criteria (LV dilation adjusted for body size + LV systolic dysfunction not explained by abnormal loading conditions or coronary artery disease) apply; differential diagnosis must exclude ischemic cardiomyopathy, myocarditis, toxic/metabolic cardiomyopathy, and other genetic causes (LMNA, TTN, MYH7, BAG3, FLNC, etc.) before attributing disease to TPM1.
• Screening: First-degree relatives of a confirmed CMD1Y proband should undergo clinical (echocardiographic) and/or genetic cascade screening given autosomal dominant inheritance and documented within-family segregation in reported pedigrees.

11. Outcome/Prognosis

• CMD1Y carries a variable but potentially severe prognosis: OMIM describes death from progressive cardiac failure in the third to sixth decades in some patients OMIM #611878; the E54K variant was originally identified in a 27-year-old man who died awaiting cardiac transplantation (per OMIM/Olson et al. 2001); the K30E de novo variant caused death at 3 years 8 months in a pediatric patient despite treatment (PMID 39684770).
• Complications: Progressive heart failure, arrhythmia (documented risk generically in DCM; specific arrhythmia burden not separately quantified for TPM1 carriers in this search), and need for advanced therapies (transplantation) in severe cases.
• Prognostic factors: Age of onset appears prognostically important — neonatal/early pediatric onset (as with de novo K30E) is associated with rapid, fatal progression, whereas adult-onset cases (E114Q) can show symptomatic improvement with standard heart-failure pharmacotherapy (beta-blocker) at one-year follow-up.
• No formal survival-curve or actuarial life-expectancy data specific to CMD1Y were identified; prognosis should be extrapolated cautiously from the general sarcomeric-DCM literature, where genotype (e.g., LMNA, FLNC, PLN, TTN) is increasingly used for arrhythmic risk stratification — TPM1 is not among the genes currently flagged for enhanced primary-prevention ICD thresholds in contemporary guidelines, unlike LMNA/FLNC/PLN.

12. Treatment

No CMD1Y-specific therapy exists; management follows standard guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction, as used in the reported cases:

• Pharmacotherapy (documented in CMD1Y case reports):
• Beta-blocker (metoprolol) — improved symptoms at 1-year follow-up in the E114Q adult case (NCIT:C15986 Pharmacotherapy; specific agent metoprolol)
• ACE inhibitor (captopril) — used in the pediatric K30E case
• Loop diuretic (furosemide) and mineralocorticoid receptor antagonist (spironolactone) — used in the K30E case for volume management
• Digoxin — used in the K30E case
• Electrolyte/cardioprotective supplementation (potassium, magnesium)
• Broader GDMT framework applicable to DCM generally (not CMD1Y-specific but standard of care): ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor–neprilysin inhibitor (ARNI), per contemporary heart-failure guidelines; SGLT2 inhibitors are now also part of standard quadruple therapy for HFrEF broadly (not specifically documented in the TPM1 case literature reviewed, but standard of care as of current guidelines).
• Device therapy: Implantable cardioverter-defibrillator (ICD) for symptomatic ventricular arrhythmia, resuscitated sudden cardiac death, or per standard EF-based primary-prevention criteria; cardiac resynchronization therapy (CRT) as indicated by QRS/conduction criteria in advanced disease.
• Advanced/end-stage therapy: Ventricular assist device (VAD) and/or cardiac transplantation for refractory heart failure — directly relevant, as the original E54K CMD1Y patient died awaiting transplantation.
• Suggested NCIT terms:
• NCIT:C15986 — Pharmacotherapy
• NCIT:C15747 — Supportive Care
• NCIT:C15289 — Organ Transplantation (cardiac transplantation)
• Device-based therapy (ICD/CRT — no precise NCIT clinical-action term readily available; would need therapeutic_modality: DEVICE)
• Experimental/precision approaches: No TPM1/CMD1Y-specific gene therapy, ASO, or targeted molecular therapy identified in current trials; myofilament-targeted small molecules (e.g., myosin modulators developed for HCM) are mechanistically informative but not established/approved therapies for TPM1-DCM specifically.
• Genetic counseling: Recommended given autosomal dominant inheritance and demonstrated family segregation (NCIT:C15240 — Genetic Counseling).

13. Prevention

• Primary prevention: Not applicable in the traditional sense (monogenic disease); the closest analog is genetic/family counseling to identify at-risk relatives before symptom onset.
• Secondary prevention/screening: Cascade genetic testing of first-degree relatives once a proband's TPM1 variant is confirmed, paired with periodic clinical (echocardiographic) surveillance of genotype-positive, phenotype-negative relatives — standard practice for genetic DCM generally, though no CMD1Y-specific screening protocol/interval was identified in this search.
• Tertiary prevention: Early initiation of GDMT in genotype-positive/pre-clinical individuals is an area of active general-DCM management interest but is not specifically validated for TPM1 carriers in the literature reviewed.
• Reproductive options: Prenatal/preimplantation genetic testing could be considered for known familial variants, consistent with general practice for highly penetrant autosomal dominant cardiomyopathies, though not specifically documented for CMD1Y.

14. Other Species / Natural Disease

• Taxonomy: TPM1 orthologs are broadly conserved across vertebrates. Mouse ortholog: Tpm1 (MGI:98809), "tropomyosin 1, alpha."
• Natural disease in other species: No naturally occurring TPM1-associated cardiomyopathy in companion animals or wildlife was identified in this search (unlike, e.g., some MYBPC3-associated feline HCM); this appears to be an under-studied area for veterinary comparative pathology.
• Comparative biology: The tropomyosin–troponin–actin regulatory apparatus is deeply conserved across striated muscle in all vertebrates, supporting strong evolutionary conservation of the core disease mechanism (calcium-regulated thin-filament activation).

15. Model Organisms

• Cellular/in vitro models: The most current and mechanistically informative CMD1Y-relevant models are human iPSC-derived cardiomyocytes and engineered heart tissue, used to directly compare DCM-causing (E54K) versus HCM-causing (E62Q) TPM1 variants and demonstrate divergent contractile phenotypes (hypocontractility vs. hypercontractility) (PMID: 39436707, J Clin Invest, 2024). Recombinant mutant tropomyosin protein combined with in vitro motility assays and differential scanning calorimetry has also been used to characterize specific variants biophysically (e.g., K30E, PMID 39684770; D230N, PMID 28600229).
• Computational models: Myofilament/sarcomere computational modeling has been used alongside iPSC-CM data to mechanistically dissect how TPM1 variants shift the contractile force–calcium relationship (PMID 39436707); separately, myofilament modeling approaches for predicting tropomyosin mutation effects on cardiac contraction have been described generally (PMC5081029).
• Animal models: No CMD1Y (TPM1-DCM)-specific transgenic/knock-in mouse or zebrafish model was identified in this search (searches for TPM1 E54K/E40K knock-in mice or zebrafish models did not return a CMD1Y-specific in vivo model; the field currently relies predominantly on iPSC-CM and biophysical reconstitution systems for TPM1-DCM). This is a notable knowledge gap relative to other DCM genes (e.g., TNNT2 R141W, LMNA, and titin-based DCM, which all have established mouse knock-in models cited in the general DCM literature) — worth flagging explicitly as a HUMAN_MODEL_MISMATCH/knowledge-gap candidate in a dismech entry, since in vivo whole-organism validation of TPM1-DCM mechanisms is currently lacking relative to the strength of the in vitro/computational mechanistic data.
• Model limitations: iPSC-CM/engineered heart tissue systems capture sarcomeric contractile mechanics well but do not recapitulate whole-organ chamber remodeling, neurohormonal compensation, or long-term arrhythmic risk — meaning the "hypocontractility → dilation" causal link, while mechanistically well-supported at the cell/tissue level, has not been confirmed in an intact-organ in vivo model specific to CMD1Y.

Summary of Key Ontology Term Suggestions for KB Curation

Sources

• OMIM #611878 — CARDIOMYOPATHY, DILATED, 1Y; CMD1Y
• OMIM *191010 — TROPOMYOSIN 1; TPM1
• MedGen C2678476 — Dilated cardiomyopathy 1Y
• NIH GTR — Dilated cardiomyopathy 1Y
• Olson TM et al., "Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy," PMID: 11273725
• "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy," PMID: 28600229
• ClinVar RCV000036354 — TPM1 D230N / Primary dilated cardiomyopathy
• ClinVar RCV000036318 — TPM1 M8R / Primary dilated cardiomyopathy
• "Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy," PMID: 39684770
• "Identification of a novel missense mutation in the TPM1 gene via exome sequencing in a Chinese family with dilated cardiomyopathy," PMID: 35029218
• "Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy–associated TPM1 variants," J Clin Invest, PMID: 39436707 (2024)
• "In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R," PMC11392859
• "GENETIC CAUSES OF DILATED CARDIOMYOPATHY," PMC4288017
• "Epidemiology — Dilated Cardiomyopathy," NCBI Bookshelf NBK553847
• "Family Screening in Dilated Cardiomyopathy: Prevalence, Incidence, and Potential for Limiting Follow-Up," JACC: Heart Failure (2022), https://www.jacc.org/doi/10.1016/j.jchf.2022.07.009
• "Current Management and Treatment — Dilated Cardiomyopathy," NCBI Bookshelf NBK553842
• Orphanet — TPM1 gene-disease associations (ORPHA:154, ORPHA:54260, ORPHA:155)
• TPM1 gene, GenCC / ClinGen curation, https://thegencc.org/genes/HGNC:12010
• MGI — Tpm1 mouse gene detail, MGI:98809

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