🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant HP:0000006

ClinGen curated the relationship under autosomal dominant inheritance. Zygosity is stated explicitly only for the Trachoo E191K subject (heterozygous); the other reports do not state zygosity in the cited text. Penetrance cannot be estimated. No segregating dilated-cardiomyopathy family is described in the cached sources, and the founding allele W4R is common in the population and failed to segregate in the one family where it was tested.

Autosomal dominant inheritance Penetrance: UNKNOWN

Show evidence (1 reference)

CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z SUPPORT Other

Records the mode of inheritance (AD) that the expert panel curated.

?

Discussions and Knowledge Gaps

3

Is CMD1M a real Mendelian dilated cardiomyopathy, or a locus built on a common variant and a few unsegregated probands?

KNOWLEDGE GAP OPEN cmd1m_entity_validity

Attached to

genetic#CSRP3 disease#Dilated Cardiomyopathy 1M

The human case rests on W4R (common, and non-segregating in one family), K69R (one patient) and single probands from cohort screens. No segregating dilated-cardiomyopathy pedigree is described in the cached sources, and a 945-case burden comparison found no excess of rare CSRP3 variants. ClinGen's Limited rating means the relationship has not been ruled out, and MLP biology makes dilated cardiomyopathy plausible. The gap would close with segregation of a rare CSRP3 variant in a dilated-cardiomyopathy family, or a burden signal in a large cohort.

Show evidence (3 references)

PMID:14567970 REFUTE PRIMARY RESULT Human Clinical

"In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family."

The founding allele failed to segregate.

PMID:27532257 REFUTE PRIMARY RESULT Human Clinical

"CSRP3 945 60647 0.00029 1.10 (0.35–3.45) 0.09 (0.00–0.71) 0.00070 2.92 (0.39–21.6) 0.66 (0.00–0.95)"

No case excess for CSRP3 in dilated cardiomyopathy.

CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z SUPPORT Other

The expert panel still rates the relationship Limited, not Disputed.

Why does loss of MLP give dilated cardiomyopathy in the knockout mouse but mainly hypertrophic cardiomyopathy in humans, in the W4R knock-in mouse and in human stem-cell cardiomyocytes?

HUMAN MODEL MISMATCH OPEN cmd1m_mouse_dilated_human_hypertrophic

Attached to

animal_models#Csrp3 (Mlp) knockout mouse pathophysiology#Left Ventricular Dilation and Systolic Dysfunction

Most of the mechanistic chain in this entry comes from the MLP-null mouse. In humans, CSRP3 is a Definitive hypertrophic-cardiomyopathy gene, and biallelic truncating variants give adult hypertrophic cardiomyopathy. Knock-in of the founding dilated allele gives hypertrophic cardiomyopathy in mice, and MLP-null human ESC-derived cardiomyocytes develop hypertrophic features. The MLP-null mouse itself has hypertrophy along with dilation. So the dilated outcome may reflect mouse strain, complete null dose, or a late dilated phase of a hypertrophic process, rather than a distinct dilated mechanism.

Show evidence (5 references)

PMID:20044516 SUPPORT PRIMARY RESULT Model Organism

"We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under..."

The founding dilated allele gives hypertrophic cardiomyopathy in mice.

PMID:31406109 SUPPORT PRIMARY RESULT In Vitro

"MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure."

Human MLP-null cardiomyocytes take on hypertrophic features.

PMID:38666070 SUPPORT REVIEW SYNTHESIS Human Clinical

"Conversely, biallelic PTVs in CSRP3 are seemingly associated with HCM in adults (based on six reported cases)"

Near-complete human loss of CSRP3 gives hypertrophic cardiomyopathy, unlike the knockout mouse.

+ 2 more references

Is the phospholamban-SERCA2a calcium-cycling defect a primary driver of MLP-deficient cardiomyopathy, or does phospholamban ablation rescue it by acting around a primary mechanosensing defect?

CONTROVERSY OPEN cmd1m_calcium_vs_mechanosensing

Attached to

pathophysiology#Sarcoplasmic Reticulum Calcium Cycling Defect pathophysiology#Defective Cardiomyocyte Stretch Sensing

The 1999 rescue paper concluded that progressive dilation depends on an SR calcium-cycling defect. The MLP group's later review notes that MLP-null hearts have normal or enhanced SERCA function. It proposes that the rescue works through mechanosensation, calcium sensitivity or passive stiffness instead. Human stem-cell data again point to calcium, but in a hypertrophic context. This entry keeps both branches, with the calcium node marked HYPOTHETICAL.

Show evidence (3 references)

PMID:10555147 SUPPORT PRIMARY RESULT Model Organism

"Via complementation of a genetically based mouse model of dilated cardiomyopathy, we now provide evidence that progressive chamber dilation and heart failure are dependent on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum."

The calcium-primacy position.

PMID:21484537 REFUTE REVIEW SYNTHESIS Model Organism

"The stunning improvement of function in these double transgenic mouse models is not solely due to improved calcium metabolism because MLP-deficient animals exhibit normal or enhanced sacroplasmic reticulum calcium ATPase (SERCA) function [50]"

The counter-position.

PMID:21484537 SUPPORT REVIEW SYNTHESIS Other

"Although considerable efforts have been undertaken to unravel the underlying molecular mechanisms-how MLP mutations, either in model organisms or in the human setting cause these diseases are still unclear."

The field's own statement that the mechanism remains unresolved.

⚙

Pathophysiology

9

Heterozygous CSRP3 Missense Variant

Mechanism confidence: Provisional

The proposed initiating lesion is a heterozygous germline missense variant in CSRP3. The reported dilated-cardiomyopathy alleles are W4R in the N-terminus and K69R, which lies in a conserved region next to the first LIM domain that is involved in alpha-actinin binding. W4R is a common European allele that did not segregate with disease in the one family where segregation was tested. Whether either allele causes dilated cardiomyopathy on its own is unresolved (see the discussions).

Cardiomyocyte CL:0000746

CSRP3 hgnc:2472

Downstream

Loss of MLP Binding to Telethonin and Alpha-Actinin-2 Each reported dilated-cardiomyopathy allele weakens or abolishes binding of MLP to a Z-disc partner when tested experimentally.

Reduced Myocardial MLP Abundance The W4R allele lowers MLP mRNA and protein in knock-in mouse hearts. In human HCM hearts, at least one CSRP3 missense protein appears destabilised. No measurement exists in human CMD1M myocardium.

Show evidence (3 references)

PMID:12507422 SUPPORT PRIMARY RESULT Human Clinical

"Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization."

The founding report of a CSRP3 variant in human dilated cardiomyopathy. Graded HUMAN_CLINICAL for the patient association it reports. The interaction defect in the same sentence is cited separately as in vitro evidence on the downstream node.

PMID:14567970 SUPPORT PRIMARY RESULT Human Clinical

"We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R)."

The second reported dilated-cardiomyopathy allele, in a single patient.

PMID:14567970 REFUTE INDIRECT PRIMARY RESULT Human Clinical

"In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family."

Applies to the W4R allele only, not to the node as a whole: non-segregation of the founding W4R allele weakens the claim that W4R alone initiates dilated cardiomyopathy. K69R and G72R are untested for segregation.

Loss of MLP Binding to Telethonin and Alpha-Actinin-2

Mechanism confidence: Provisional

MLP binds telethonin (T-cap), which in turn binds the N-terminus of titin, and alpha-actinin-2, the main Z-disc actin cross-linker. W4R weakens the telethonin interaction and K69R abolishes the alpha-actinin-2 interaction. In the founding study, telethonin was lost from the Z-disc in a subset of MLP-null mouse cardiomyocytes and in myocardial biopsies from W4R carriers. A dilated-cardiomyopathy variant in the partner, ACTN2 Q9R, also disrupts MLP binding, which supports the view that this complex is the relevant one.

Cardiomyocyte CL:0000746

CSRP3 hgnc:2472

Telethonin binding GO:0031433 ↓ DECREASED Muscle alpha-actinin binding GO:0051371 ↓ DECREASED

Z disc GO:0030018

Downstream

Defective Cardiomyocyte Stretch Sensing Loss of the Z-disc MLP/telethonin complex is proposed to disable stretch sensing in the cardiomyocyte.

Show evidence (4 references)

PMID:12507422 SUPPORT PRIMARY RESULT In Vitro

"MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein."

Establishes the MLP-telethonin interaction that the W4R allele disrupts.

PMID:14567970 SUPPORT PRIMARY RESULT In Vitro

"Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered."

K69R abolishes alpha-actinin-2 binding and changes where MLP sits in the cell.

PMID:21484537 SUPPORT REVIEW SYNTHESIS Human Clinical

"In this regard, we observed loss of telethonin at the Z-disc in a subset of MLP−/− cardiomyocytes as well as in myocardial biopsies from patients carrying the W4R-MLP mutation, which is supported by our finding that W4R-MLP binds with less affinity to telethonin [26, 27]."

The review's summary of the founding group's own work, including the only human myocardial observation of the binding defect: telethonin lost from the Z-disc in biopsies from W4R carriers. Graded HUMAN_CLINICAL for that biopsy finding. The MLP-null part of the sentence is mouse data.

+ 1 more reference

Reduced Myocardial MLP Abundance

Mechanism confidence: Hypothetical

A lower dose of functional MLP in the myocardium. W4R knock-in mice have reduced MLP mRNA and protein, and heterozygous MLP+/- mice show that halving MLP is enough to worsen remodeling under stress. Whether human CMD1M variants reduce myocardial MLP has not been measured. The node is HYPOTHETICAL for that reason.

Cardiomyocyte CL:0000746

Animal models

Mlp W4R knock-in mouse Mouse recapitulates Carries the human allele and lowers MLP in the heart.

Downstream

Disrupted Cardiomyocyte Cytoarchitecture Complete loss of MLP disrupts cardiomyocyte cytoarchitecture in the mouse. Whether a partial reduction does the same in human myocardium is not known.

Impaired Z-Disc Calcineurin-NFAT Stress Signalling In heterozygous MLP+/- mice, halving MLP displaces calcineurin from the Z-disc and blunts stress-induced NFAT activation.

Sarcoplasmic Reticulum Calcium Cycling Defect In MLP-null mice, ablating phospholamban rescues the cardiomyopathy. This implicates phospholamban-SERCA2a inhibition in disease progression. How loss of MLP produces that calcium-cycling defect is not established.

Show evidence (1 reference)

PMID:20044516 SUPPORT PRIMARY RESULT Model Organism

"Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals."

Reduced MLP in W4R knock-in mouse hearts.

Defective Cardiomyocyte Stretch Sensing

Mechanism confidence: Provisional

MLP-null cardiomyocytes fail to induce brain natriuretic peptide in response to mechanical stretch, yet still respond to endothelin-1 or phenylephrine. That pattern places MLP upstream in the stretch-specific signalling pathway. The defect has been shown in mouse and rat cardiomyocytes and in W4R knock-in cells, not in human CMD1M tissue.

Cardiomyocyte CL:0000746

Detection of muscle stretch GO:0035995 ↓ DECREASED Cellular response to mechanical stimulus GO:0071260 ↓ DECREASED

Downstream

Left Ventricular Dilation and Systolic Dysfunction Loss of stretch sensing is proposed to leave the myocardium unable to adapt to hemodynamic load, ending in chamber dilation. The intermediate steps are not mapped.

Show evidence (3 references)

PMID:12507422 SUPPORT PRIMARY RESULT Model Organism

"Here, we present biophysical/biochemical studies in muscle LIM protein (MLP) deficient cardiac muscle that support a selective role for this Z disc protein in mechanical stretch sensing."

Direct evidence, from MLP-deficient cardiac muscle, that MLP takes part in stretch sensing.

PMID:21484537 SUPPORT REVIEW SYNTHESIS Model Organism

"are defective upon mechanical stimulation in brain natriuretic peptide (BNP) induction, which is an important indicator of cell stretch, whereas endothelin 1 or phenylephrine (PE) were still able to induce BNP expression in these cells"

The subject of this sentence in the review is MLP-null isolated cardiomyocytes. It shows the defect is specific to stretch: agonist-induced BNP expression is preserved.

PMID:21484537 SUPPORT REVIEW SYNTHESIS In Vitro

"A similar defect in BNP gene expression following stretch in an in vitro cell culture system has also been obtained when the W4R-MLP mutation"

The sentence continues that the W4R allele was analysed in a knock-in mouse model: cultured cardiomyocytes carrying the human allele show the same stretch-specific BNP defect, so the allele itself, not only complete MLP loss, impairs stretch sensing. The quote stops before the sentence's parenthetical about human carriers, which is cited separately.

Impaired Z-Disc Calcineurin-NFAT Stress Signalling

Mechanism confidence: Hypothetical

MLP anchors calcineurin at the Z-disc. When MLP is reduced, calcineurin is displaced and stress-induced calcineurin-NFAT activation is blunted. Calcineurin is protective in this setting: deleting calcineurin A-beta in MLP-null mice worsens the cardiomyopathy, and activated calcineurin improves it. All evidence for this node is from mice and cultured cardiomyocytes.

Cardiomyocyte CL:0000746

Calcineurin-NFAT signaling cascade GO:0033173 ↓ DECREASED

Z disc GO:0030018

Animal models

Heterozygous Csrp3 (MLP+/-) mouse after myocardial infarction Mouse recapitulates Shows calcineurin displacement and blunted NFAT activation with a reduced MLP dose.

Downstream

Left Ventricular Dilation and Systolic Dysfunction With reduced MLP-calcineurin signalling, the ventricle remodels badly under stress and dilates.

Show evidence (2 references)

PMID:15665106 SUPPORT PRIMARY RESULT Model Organism

"Our study reveals a link between the stress sensor MLP and the calcineurin-NFAT pathway at the sarcomeric Z-disk in cardiomyocytes and indicates that reduced MLP-calcineurin signaling predisposes to adverse remodeling after MI."

Links MLP to calcineurin-NFAT signalling at the Z-disc.

PMID:19854199 SUPPORT PRIMARY RESULT Model Organism

"Antithetically, mild overexpression of activated calcineurin in the mouse heart improved function and adverse remodeling in MLP knock-out mice."

Restoring calcineurin activity improves MLP-null cardiomyopathy, so loss of calcineurin signalling contributes to the phenotype.

Disrupted Cardiomyocyte Cytoarchitecture

Mechanism confidence: Hypothetical

Without MLP, cardiomyocyte cytoarchitecture is disorganised at the ultrastructural level, and newborn hearts are abnormally soft before any hypertrophy develops. MLP deficiency also causes a defect in passive elasticity, which precedes global heart failure. These findings come from the knockout mouse.

Cardiomyocyte CL:0000746

Sarcomere organization GO:0045214 ⚠ ABNORMAL

Animal models

Csrp3 (Mlp) knockout mouse Mouse recapitulates The structural lesion that the cytoarchitecture node is built on.

Downstream

Left Ventricular Dilation and Systolic Dysfunction Disorganised cytoarchitecture is the knockout paper's stated route to dilated cardiomyopathy.

Show evidence (2 references)

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture."

The ultrastructural lesion in MLP-null hearts.

PMID:21484537 SUPPORT REVIEW SYNTHESIS Model Organism

"Another important aspect was the significant defect in passive elasticity under MLP deficiency, which is probably responsible for the diastolic dysfunction observed in these animals before they develop global heart failure."

A mechanical correlate of the structural lesion, present before heart failure.

Sarcoplasmic Reticulum Calcium Cycling Defect

Mechanism confidence: Hypothetical

Chronic inhibition of SERCA2a by phospholamban has been proposed as the calcium-cycling defect that drives chamber dilation in the MLP-null mouse, because ablating phospholamban rescues the phenotype. MLP-null hearts, however, are reported to have normal or enhanced SERCA function. The rescue may therefore work by bypassing the MLP lesion rather than by correcting it. MLP-null human stem-cell cardiomyocytes also show abnormal calcium handling, but they model hypertrophic rather than dilated disease. The node is HYPOTHETICAL for CMD1M.

Cardiomyocyte CL:0000746

Sarcoplasmic reticulum calcium ion transport GO:0070296 ⚠ ABNORMAL

Animal models

MLP-null and phospholamban-null double knockout mouse Mouse rescues Relieving SERCA2a inhibition by removing phospholamban rescues the MLP-null cardiomyopathy.

Downstream

Left Ventricular Dilation and Systolic Dysfunction In the mouse model, progressive chamber dilation depends on the SR calcium-cycling defect.

Show evidence (2 references)

PMID:10555147 SUPPORT PRIMARY RESULT Model Organism

"The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure."

Phospholamban ablation rescues the mouse dilated-cardiomyopathy model. A review confirms that the model was the MLP-null mouse (see the incoming edge).

PMID:31406109 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a central mechanism for pathogenesis of MLP deficiency."

Human-cell evidence that MLP loss disturbs calcium homeostasis. INDIRECT because the phenotype is HCM-like rather than dilated, and the cells are a full knockout rather than a patient allele.

Left Ventricular Dilation and Systolic Dysfunction

Mechanism confidence: Provisional

The defining remodeling of dilated cardiomyopathy: an enlarged left ventricle with falling systolic function. In the MLP-null mouse it develops after birth and is accompanied by hypertrophy. Human CMD1M reports describe dilated cardiomyopathy without further structural detail in their abstracts.

Cardiomyocyte CL:0000746

Heart contraction GO:0060047 ↓ DECREASED

Left ventricle UBERON:0002084

Animal models

Csrp3 (Mlp) knockout mouse Mouse partially recapitulates Produces dilated cardiomyopathy and heart failure that resemble the human clinical picture.

Mlp W4R knock-in mouse Mouse fails to recapitulate The founding dilated-cardiomyopathy allele produces hypertrophic, not dilated, cardiomyopathy in the mouse.

Downstream

Heart Failure Progressive dilation and systolic dysfunction lead to heart failure.

Dilated Cardiomyopathy Left ventricular dilation with systolic dysfunction is the clinical phenotype of dilated cardiomyopathy.

Show evidence (2 references)

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth."

The ventricular phenotype of the MLP-null mouse.

PMID:12507422 SUPPORT PRIMARY RESULT Human Clinical

"Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization."

The human dilated-cardiomyopathy phenotype that the founding CSRP3 allele was reported with.

Heart Failure

Mechanism confidence: Provisional

Clinical pump failure from the dilated, poorly contracting ventricle. It is the reported outcome in the MLP-null mouse, and W4R carriers have been described with cardiomyopathy and heart failure.

Heart contraction GO:0060047 ⚠ ABNORMAL

Downstream

Congestive Heart Failure The organism-level failure appears clinically as congestive heart failure.

Show evidence (1 reference)

PMID:21484537 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"the W4R-MLP mutation, observed in human individuals affected by cardiomyopathy and heart failure"

The review's description of the human W4R carriers, which includes heart failure. INDIRECT because the phrase is a parenthetical inside a sentence about a knock-in mouse experiment, and it says "cardiomyopathy" without specifying dilated cardiomyopathy.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

3

Dilated Cardiomyopathy Cardiovascular HP:0001644

No frequency band is assigned. Dilated cardiomyopathy is the ascertainment criterion for every reported case, so a frequency would be circular.

Show evidence (2 references)

PMID:12507422 SUPPORT PRIMARY RESULT Human Clinical

"Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization."

Dilated cardiomyopathy is the phenotype the founding CSRP3 allele was reported with.

PMID:14567970 SUPPORT PRIMARY RESULT Human Clinical

"We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R)."

Dilated cardiomyopathy in the K69R patient.

Congestive Heart Failure Cardiovascular HP:0001635

No frequency is assigned because the cached sources give no denominator for heart failure among CSRP3 dilated-cardiomyopathy carriers.

Show evidence (1 reference)

PMID:21484537 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"the W4R-MLP mutation, observed in human individuals affected by cardiomyopathy and heart failure"

Heart failure in human W4R carriers, as summarised by the group that reported the allele. INDIRECT because the phrase is a parenthetical inside a sentence about a knock-in mouse experiment, and it says "cardiomyopathy" without specifying dilated cardiomyopathy.

Endocardial Fibroelastosis Cardiovascular HP:0001706

Seen in one patient. No frequency is assigned. The phenotype is left unconnected in the pathograph because no cited source proposes a mechanism linking MLP to endocardial fibroelastosis.

Show evidence (1 reference)

PMID:14567970 SUPPORT PRIMARY RESULT Human Clinical

"We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R)."

Endocardial fibroelastosis in the K69R patient.

🧬

Genetic Associations

1

CSRP3 (Heterozygous CSRP3 missense variants reported in dilated cardiomyopathy (W4R, K69R and single variants from cohort screens). The relationship is classified Limited by ClinGen. relationship_type is left unset because CAUSATIVE is reserved for Definitive or Strong relationships.)

Gene: CSRP3 hgnc:2472 gene page variant_origin: GERMLINE

Show evidence (4 references)

CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z SUPPORT Other

The current expert-panel classification for this gene and this disease.

PMID:20044516 SUPPORT PRIMARY RESULT Human Clinical

"Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that (W4R-MLP) might contribute significantly to human cardiovascular disease."

States the population frequency of W4R. The authors read it as a common contributor to cardiovascular disease. That frequency also makes W4R implausible as a penetrant monogenic cause of a rare cardiomyopathy.

PMID:18505755 REFUTE BACKGROUND Human Clinical

"Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations."

The 2008 linkage study that confirmed CSRP3 as an HCM gene judged the earlier dilated-cardiomyopathy reports to lack comprehensive genetic evidence for causation. The parent Dilated_Cardiomyopathy entry cites the same sentence.

+ 1 more reference

Variants (4)

CSRP3 p.Trp4Arg (W4R)

The founding allele, c.10T>C in exon 2 according to the 2010 knock-in paper. It weakens telethonin binding and lowers MLP levels in knock-in mice. It is carried by up to 1% of people of European ancestry and did not segregate with dilated cardiomyopathy in the one family where segregation was tested. On current evidence it is best read as a common low-penetrance or benign variant, not a monogenic cause of this disease.

CSRP3 p.Lys69Arg (K69R)

Reported in one patient with dilated cardiomyopathy and endocardial fibroelastosis. It sits in a conserved region next to the first LIM domain and abolishes alpha-actinin-2 binding in cell culture. Segregation is not reported in the abstract.

CSRP3 p.Gly72Arg (G72R)

The single CSRP3 variant among 313 dilated-cardiomyopathy probands in Hershberger 2008. It replaces a conserved residue and was judged possibly disease-causing.

CSRP3 p.Glu191Lys (E191K)

NM_003476.5:c.571G>A, heterozygous, in one of 31 dilated-cardiomyopathy subjects in a Thai clinical series (Trachoo 2022), classified as a variant of uncertain significance.

💊

Medical Actions

3

Guideline-Directed Heart Failure Therapy

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Management follows standard guideline-directed therapy for dilated cardiomyopathy and heart failure with reduced ejection fraction. No CSRP3-specific therapy or trial exists.

Mechanism Target:

Heart Failure — Acts on the heart-failure end of the chain, not on the MLP lesion.

Show evidence (1 reference)

PMID:35379503 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients' interests."

The guideline that management follows. INDIRECT because it is written for heart failure in general and does not mention CSRP3.

Cardiac Transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

The usual option for refractory end-stage dilated cardiomyopathy.

Mechanism Target:

Heart Failure — Replaces the failing organ. It does not address the mechanism.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Counseling should explain that the CSRP3 dilated-cardiomyopathy relationship is Limited, so a CSRP3 variant alone does not justify predictive testing of relatives. Clinical (echocardiographic) screening of first-degree relatives follows general familial dilated-cardiomyopathy practice.

Show evidence (1 reference)

PMID:33947203 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."

The basis for advising caution about acting on a CSRP3 result. INDIRECT because the abstract does not name CSRP3.

🔬

Diagnosis

2

Clinical Evaluation for Nonsyndromic Dilated Cardiomyopathy

The phenotype is established clinically, with imaging showing a dilated, poorly contracting left ventricle after ischaemic, valvular and other acquired causes have been excluded. No imaging, biopsy or biomarker feature specific to CSRP3 has been reported.

Show evidence (1 reference)

PMID:20301486 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Provide the evaluation strategy of a proband with nonsyndromic DCM"

The GeneReviews overview sets out how to evaluate a dilated-cardiomyopathy proband. It is INDIRECT because it covers the disease class, not CSRP3.

Multigene Cardiomyopathy Panel Testing

CSRP3 appears on many dilated-cardiomyopathy panels. At a Limited classification, a CSRP3 variant found in a dilated-cardiomyopathy proband should not be reported as a molecular diagnosis on its own. W4R in particular is too common to be interpreted as causal. Testing is most useful for finding a variant in a high-evidence gene.

Show evidence (2 references)

PMID:33947203 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes."

The expert recommendation that applies to a Limited gene such as CSRP3. INDIRECT because the abstract does not name CSRP3.

PMID:27532257 SUPPORT PRIMARY RESULT Human Clinical

"We found that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative because there is an unacceptably high likelihood of false-positive interpretation."

The study that found no CSRP3 enrichment in dilated cardiomyopathy concludes that rare variants in genes like this one are prone to false-positive interpretation.

📊

Prevalence

1

Dilated cardiomyopathy probands with a reported CSRP3 variant

Cases In Literature Not yet documented

No population prevalence exists for CMD1M. The cited sources describe a handful of dilated-cardiomyopathy probands with a CSRP3 variant, and none reports a multigenerational family in which a CSRP3 variant segregates with dilated cardiomyopathy. Counted from those sources: (1) the founding Knoll 2002 report of W4R in dilated cardiomyopathy, with no patient count in the abstract; (2) Mohapatra 2003, one patient with dilated cardiomyopathy and endocardial fibroelastosis carrying K69R, and one individual with dilated cardiomyopathy carrying W4R in a family where the variant did not segregate with disease; (3) Hershberger 2008, one proband (0.3%) out of 313 sequenced dilated-cardiomyopathy patients, carrying G72R; and (4) Trachoo 2022, one of 31 dilated-cardiomyopathy subjects, heterozygous for E191K (c.571G>A) and classified as a variant of uncertain significance. Against this, a 945-case burden comparison found no detectable excess of rare CSRP3 variants in dilated cardiomyopathy (odds ratio 1.10; a modest effect is not excluded). The W4R allele is far more common in the population (up to 1% of people of European ancestry) than the disease could be if W4R were a penetrant dominant cause. The prevalence class is NOT_YET_DOCUMENTED because no rate has been measured. The phrase "extremely rare, if it exists as a distinct entity" is a qualitative judgement, not a measured tier.

Show evidence (7 references)

PMID:14567970 SUPPORT PRIMARY RESULT Human Clinical

"We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R)."

One proband with dilated cardiomyopathy and endocardial fibroelastosis carrying K69R.

PMID:14567970 SUPPORT PRIMARY RESULT Human Clinical

"In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family."

A second dilated-cardiomyopathy proband, carrying W4R. The variant did not segregate with disease, so this case counts as a reported carrier, not as a segregating family.

PMID:19412328 SUPPORT PRIMARY RESULT Human Clinical

"three probands (1.0%) with two LIM domain binding 3 (LDB3) mutations, and one proband (0.3%) with a muscle LIM protein (CSRP3) mutation"

One CSRP3 proband among 313 sequenced dilated-cardiomyopathy patients. This is the yield of a screen in a selected cohort, not a population prevalence.

+ 4 more references

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1M:

Hypertrophic Cardiomyopathy 12 MONDO:0012804

Overlapping Features The allelic CSRP3 disorder (CMH12), and the better-established one. CSRP3 missense variants segregate with hypertrophic cardiomyopathy in several families, and ClinGen rates CSRP3 for hypertrophic cardiomyopathy as Definitive with semi-dominant inheritance. Biallelic CSRP3 truncating variants have been reported in adult hypertrophic cardiomyopathy. A CSRP3 carrier with a dilated ventricle needs hypertrophic cardiomyopathy with later dilation considered. dismech curates CSRP3 hypertrophic disease on the Hypertrophic_Cardiomyopathy entry. CMH12 itself is still a stub.

Distinguishing Features

Unexplained left ventricular hypertrophy rather than primary dilation. In the HCM carriers of the 2008 study there was also evidence of mild skeletal muscle disease.

Show evidence (5 references)

PMID:18505755 SUPPORT PRIMARY RESULT Human Clinical

"We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene."

Linkage evidence establishing CSRP3 as a hypertrophic-cardiomyopathy gene.

PMID:18505755 SUPPORT PRIMARY RESULT Human Clinical

"Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families."

Segregation in four more HCM families, in contrast with no segregating CMD1M family.

PMID:18505755 SUPPORT PRIMARY RESULT Human Clinical

"We also present evidence for mild skeletal muscle disease in affected persons."

Mild skeletal muscle disease in HCM carriers. It is not reported for CMD1M, so it is recorded here rather than as a CMD1M phenotype.

+ 2 more references

Dilated Cardiomyopathy 1AA MONDO:0012808

Overlapping Features ACTN2-related dilated cardiomyopathy. Alpha-actinin-2 is the Z-disc partner whose binding K69R abolishes, and a dilated-cardiomyopathy ACTN2 variant (Q9R) reported in the same 2003 screen disrupts MLP binding from the other side. The two cannot be told apart clinically; only sequencing separates them.

Distinguishing Features

The variant is in ACTN2 (alpha-actinin-2) rather than CSRP3.

Show evidence (1 reference)

PMID:14567970 SUPPORT PRIMARY RESULT Human Clinical

"In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2."

An ACTN2 variant in dilated cardiomyopathy, found in the same screen as K69R.

Dilated Cardiomyopathy MONDO:0005021

Overlapping Features Dilated cardiomyopathy from other genes or acquired causes. Because CSRP3 is a Limited gene and the founding allele is common, most CSRP3 carriers with dilated cardiomyopathy are better explained by a variant in a high-evidence gene or by an acquired cause. Ischaemic, toxic, inflammatory and peripartum dilated cardiomyopathy should be excluded clinically.

Distinguishing Features

A pathogenic variant in a Definitive or Strong dilated-cardiomyopathy gene, or an identified acquired cause.

Show evidence (1 reference)

PMID:19412328 SUPPORT PRIMARY RESULT Human Clinical

"Mutations of these six genes each account for a small fraction of the genetic cause of FDC/IDC."

CSRP3 is one of several genes that each explain only a small fraction of dilated cardiomyopathy.

🐁

Animal Models

4

Csrp3 (Mlp) knockout mouse

The classic MLP-deficient mouse, the first genetically engineered mouse model of dilated cardiomyopathy. Hearts are abnormally soft at birth, with disrupted cardiomyocyte cytoarchitecture. After birth the mice develop dilated cardiomyopathy with hypertrophy and heart failure.

Species

Mouse

Genotype

Csrp3-/- (MLP-/-), homozygous null

Publication

PMID:9039266

Pathograph links

Disrupted Cardiomyocyte Cytoarchitecture recapitulates fidelity: moderate The structural lesion that the cytoarchitecture node is built on.

Limitations: Complete loss of MLP, whereas human CMD1M carriers are heterozygous for missense alleles whose effect on MLP dose has not been measured in human myocardium.

Divergences from the human mechanism

cause unrepresented qualifying

A homozygous null does not represent a heterozygous missense variant. In humans, biallelic CSRP3 truncation gives hypertrophic rather than dilated cardiomyopathy.

Show evidence (1 reference)

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture."

The cytoarchitectural lesion in the model.

Left Ventricular Dilation and Systolic Dysfunction partially recapitulates fidelity: moderate Produces dilated cardiomyopathy and heart failure that resemble the human clinical picture.

Limitations: The dilation comes with hypertrophy, and the genotype is a complete null. The model shows that loss of MLP can cause dilated cardiomyopathy in mice. It does not show that heterozygous human CSRP3 variants do.

Divergences from the human mechanism

species mismatch qualifying

In humans, complete or near-complete loss of MLP is associated with hypertrophic, not dilated, cardiomyopathy. The direction of remodeling therefore differs between mouse and human.

Show evidence (1 reference)

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth."

Dilated cardiomyopathy and heart failure in the model, with hypertrophy.

Show evidence (1 reference)

PMID:9039266 SUPPORT PRIMARY RESULT Model Organism

"In vivo analysis revealed that MLP-deficient mice reproduce the morphological and clinical picture of dilated cardiomyopathy and heart failure in humans, providing the first model for this condition in a genetically manipulatable organism."

The authors' statement of the model's fidelity to human dilated cardiomyopathy.

Heterozygous Csrp3 (MLP+/-) mouse after myocardial infarction

Mice with half the normal MLP dose. Their hearts are normal at baseline but dilate more, and fail more, after myocardial infarction. Calcineurin is displaced from the Z-disc. This is the closest mouse analogue to a heterozygous human state.

Species

Mouse

Genotype

Csrp3+/- (MLP+/-), heterozygous null, with experimental myocardial infarction

Publication

PMID:15665106

Pathograph links

Impaired Z-Disc Calcineurin-NFAT Stress Signalling recapitulates fidelity: moderate Shows calcineurin displacement and blunted NFAT activation with a reduced MLP dose.

Limitations: The phenotype appears only after an infarction. Heterozygous null is not the same as a human missense allele.

Divergences from the human mechanism

cause unrepresented qualifying

Myocardial infarction is the stressor here. No comparable stressor is documented in human CMD1M.

Show evidence (1 reference)

PMID:15665106 SUPPORT PRIMARY RESULT Model Organism

"Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the Z-disk in MLP+/- mice, indicating that MLP is essential for calcineurin anchorage to the Z-disk."

The signalling readout in the heterozygous model.

Show evidence (1 reference)

PMID:15665106 SUPPORT PRIMARY RESULT Model Organism

"LV dimensions and function were similar in sham-operated WT and MLP+/- mice."

Heterozygous mice have no baseline phenotype. This is the main limitation of the model as a stand-alone CMD1M model.

MLP-null and phospholamban-null double knockout mouse

The MLP-null mouse crossed onto a phospholamban-null background. Removing phospholamban rescues the dilated-cardiomyopathy and heart-failure phenotype.

Species

Mouse

Genotype

Csrp3-/- Pln-/- (MLP-/- PLN-/-)

Publication

PMID:10555147

Pathograph links

Sarcoplasmic Reticulum Calcium Cycling Defect rescues fidelity: low Relieving SERCA2a inhibition by removing phospholamban rescues the MLP-null cardiomyopathy.

Limitations: A rescue does not show that the defect it corrects is the primary lesion. MLP-null hearts are reported to have normal or enhanced SERCA function, so the rescue may act around the MLP defect rather than reversing it.

Divergences from the human mechanism

contested assumption qualifying

The model assumes that the rescued calcium-cycling defect causes the MLP phenotype. Later work on SERCA function in MLP-null hearts disputes this.

Show evidence (2 references)

PMID:10555147 SUPPORT PRIMARY RESULT Model Organism

"The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure."

The rescue result.

+ 1 more reference

Show evidence (1 reference)

PMID:21484537 SUPPORT REVIEW SYNTHESIS Model Organism

"phospholamban (PLN) was ablated in MLP−/− animals and, similar to the previous study, a complete rescue effect was observed"

Confirms that the MLP-null mouse was the background for the phospholamban rescue.

Mlp W4R knock-in mouse

Knock-in of the founding CMD1M allele. Heterozygous and homozygous mice develop age- and dose-dependent hypertrophic cardiomyopathy and heart failure, lose almost all contractile reserve under catecholamine stress, and have reduced MLP and weaker telethonin binding. Some skeletal muscle pathology is also present.

Species

Mouse

Genotype

Mlp(W4R/+) and Mlp(W4R/W4R) knock-in

Publication

PMID:20044516

Pathograph links

Reduced Myocardial MLP Abundance recapitulates fidelity: moderate Carries the human allele and lowers MLP in the heart.

Limitations: This is a mouse measurement. MLP levels have not been measured in human W4R myocardium.

Show evidence (1 reference)

PMID:20044516 SUPPORT PRIMARY RESULT Model Organism

"Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals."

Reduced MLP in knock-in hearts.

Left Ventricular Dilation and Systolic Dysfunction fails to recapitulate fidelity: low The founding dilated-cardiomyopathy allele produces hypertrophic, not dilated, cardiomyopathy in the mouse.

Limitations: The opposite remodeling direction from the human entity this allele defined.

Divergences from the human mechanism

species mismatch invalidating

As a model of dilated remodeling it fails, because the knock-in develops a hypertrophic phenotype.

Show evidence (1 reference)

PMID:20044516 SUPPORT PRIMARY RESULT Model Organism

"We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under..."

The knock-in phenotype is hypertrophic cardiomyopathy.

Show evidence (1 reference)

PMID:20044516 SUPPORT PRIMARY RESULT Model Organism

"These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry."

A further cellular phenotype of the knock-in: more of the mutant protein is found in the nucleus.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1M
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: dilated cardiomyopathy 1M
  term:
    id: MONDO:0011840
    label: dilated cardiomyopathy 1M
synonyms:
- CMD1M
- cardiomyopathy, dilated, 1M
- dilated cardiomyopathy type 1M
- CSRP3-related dilated cardiomyopathy
- muscle LIM protein-related dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1M (CMD1M) is the numbered dilated-cardiomyopathy locus assigned to
  CSRP3, which encodes muscle LIM protein (MLP), a striated-muscle LIM-only protein found at the
  sarcomeric Z-disc, the costamere and the nucleus. MLP binds telethonin (T-cap) and
  alpha-actinin-2 at the Z-disc and has been proposed as part of the cardiomyocyte mechanical
  stretch sensor.

  The locus rests on a small human evidence base. The founding report (2002) described the
  N-terminal variant p.Trp4Arg (W4R) in dilated cardiomyopathy and showed that it weakens the
  MLP-telethonin interaction. A 2003 screen added p.Lys69Arg (K69R) in one patient with dilated
  cardiomyopathy and endocardial fibroelastosis; in the same screen W4R did not segregate with
  disease in a second family. W4R was later shown to be carried by up to 1% of people of European
  ancestry, and a 945-case comparison against population reference data found no detectable
  excess of rare CSRP3 variants in dilated cardiomyopathy (odds ratio 1.10; a modest effect is
  not excluded). ClinGen's Dilated Cardiomyopathy Gene Curation Expert
  Panel classifies CSRP3 for this disease as Limited (autosomal dominant).

  Most mechanistic knowledge comes from the Csrp3 (Mlp) knockout mouse, a classic model that
  develops postnatal dilated cardiomyopathy and heart failure after cytoarchitectural disruption
  of cardiomyocytes. In humans, by contrast, CSRP3 is a Definitive hypertrophic-cardiomyopathy
  gene (allelic disorder CMH12), and both the W4R knock-in mouse and MLP-null human stem-cell
  cardiomyocytes develop hypertrophic rather than dilated phenotypes. This entry records that
  mismatch rather than resolving it.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Dilated cardiomyopathy probands with a reported CSRP3 variant
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence exists for CMD1M. The cited sources describe a handful of
    dilated-cardiomyopathy probands with a CSRP3 variant, and none reports a multigenerational
    family in which a CSRP3 variant segregates with dilated cardiomyopathy. Counted from those
    sources: (1) the founding Knoll 2002 report of W4R in dilated cardiomyopathy, with no
    patient count in the abstract; (2) Mohapatra 2003, one patient with dilated cardiomyopathy
    and endocardial fibroelastosis carrying K69R, and one individual with dilated cardiomyopathy
    carrying W4R in a family where the variant did not segregate with disease; (3) Hershberger
    2008, one proband (0.3%) out of 313 sequenced dilated-cardiomyopathy patients, carrying
    G72R; and (4) Trachoo 2022, one of 31 dilated-cardiomyopathy subjects, heterozygous for
    E191K (c.571G>A) and classified as a variant of uncertain significance. Against this, a
    945-case burden comparison found no detectable excess of rare CSRP3 variants in dilated
    cardiomyopathy (odds ratio 1.10; a modest effect is not excluded). The W4R allele is far more common
    in the population (up to 1% of people of European ancestry) than the disease could be if W4R
    were a penetrant dominant cause. The prevalence class is NOT_YET_DOCUMENTED because no rate
    has been measured. The phrase "extremely rare, if it exists as a distinct entity" is a
    qualitative judgement, not a measured tier.
  evidence:
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified a patient with DCM and EFE, having a mutation in MLP with the residue
      lysine 69 substituted by arginine (K69R).
    explanation: >-
      One proband with dilated cardiomyopathy and endocardial fibroelastosis carrying K69R.
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In another individual with DCM, a W4R mutation was identified. However, this mutation did
      not segregate with disease in this family.
    explanation: >-
      A second dilated-cardiomyopathy proband, carrying W4R. The variant did not segregate with
      disease, so this case counts as a reported carrier, not as a segregating family.
  - reference: PMID:19412328
    reference_title: "Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      three probands (1.0%) with two LIM domain binding 3 (LDB3) mutations, and one proband
      (0.3%) with a muscle LIM protein (CSRP3) mutation
    explanation: >-
      One CSRP3 proband among 313 sequenced dilated-cardiomyopathy patients. This is the yield
      of a screen in a selected cohort, not a population prevalence.
  - reference: PMID:19412328
    reference_title: "Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The Gly72Arg variant predicted the replacement of a conserved amino acid and was therefore
      considered possibly disease‐causing.
    explanation: >-
      Names the allele in that proband, G72R, and records that the authors judged it only
      possibly disease-causing.
  - reference: PMID:36166435
    reference_title: "Genomic findings of hypertrophic and dilated cardiomyopathy characterized in a Thai clinical genetics service."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Among the DCM subjects, variants were detected in two cases with the TTN nonsense
      variants, while the others were missense and identified in MYH7, DRSP3, MYBPC3, and
      SCN5A.
    explanation: >-
      A CSRP3 missense variant (printed "DRSP3" in the abstract) in the 31-subject
      dilated-cardiomyopathy arm. Table 1 of the full text gives the single subject and the
      classification (next item).
  - reference: PMID:36166435
    reference_title: "Genomic findings of hypertrophic and dilated cardiomyopathy characterized in a Thai clinical genetics service."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      CSRP3 | DCM | NM_003476.5:c.571G>A | NP_003467.1:p.(Glu191Lys) | Het | Missense
    explanation: >-
      The only CSRP3 row in Table 1: one dilated-cardiomyopathy subject, heterozygous for
      E191K. The same row's final column classifies the variant as VUS.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      CSRP3 945 60647 0.00029 1.10 (0.35–3.45) 0.09 (0.00–0.71) 0.00070 2.92 (0.39–21.6)
      0.66 (0.00–0.95)
    explanation: >-
      The CSRP3 row in the dilated-cardiomyopathy section of Table 1: 945 cases against 60,647
      ExAC reference samples. The odds ratio for non-truncating variants is 1.10 (95% CI
      0.35-3.45), and the truncating-variant interval also crosses 1. There is no detectable
      excess of rare CSRP3 variation in dilated cardiomyopathy (a modest effect is not
      excluded), which is consistent with CMD1M being rare and with no rate having been
      measured.
pathophysiology:
- name: Heterozygous CSRP3 Missense Variant
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  mechanism_confidence: PROVISIONAL
  description: >-
    The proposed initiating lesion is a heterozygous germline missense variant in CSRP3. The
    reported dilated-cardiomyopathy alleles are W4R in the N-terminus and K69R, which lies in a
    conserved region next to the first LIM domain that is involved in alpha-actinin binding.
    W4R is a common European allele that did not segregate with disease in the one family where
    segregation was tested. Whether either allele causes dilated cardiomyopathy on its own is
    unresolved (see the discussions).
  genes:
  - preferred_term: CSRP3
    term:
      id: hgnc:2472
      label: CSRP3
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:12507422
    reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results
      in a marked defect in T-cap interaction/localization.
    explanation: >-
      The founding report of a CSRP3 variant in human dilated cardiomyopathy. Graded
      HUMAN_CLINICAL for the patient association it reports. The interaction defect in the same
      sentence is cited separately as in vitro evidence on the downstream node.
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified a patient with DCM and EFE, having a mutation in MLP with the residue
      lysine 69 substituted by arginine (K69R).
    explanation: >-
      The second reported dilated-cardiomyopathy allele, in a single patient.
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In another individual with DCM, a W4R mutation was identified. However, this mutation did
      not segregate with disease in this family.
    directness: INDIRECT
    explanation: >-
      Applies to the W4R allele only, not to the node as a whole: non-segregation of the
      founding W4R allele weakens the claim that W4R alone initiates dilated cardiomyopathy.
      K69R and G72R are untested for segregation.
  downstream:
  - target: Loss of MLP Binding to Telethonin and Alpha-Actinin-2
    causal_link_type: DIRECT
    description: >-
      Each reported dilated-cardiomyopathy allele weakens or abolishes binding of MLP to a
      Z-disc partner when tested experimentally.
    evidence:
    - reference: PMID:14567970
      reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Analysis in cell culture systems demonstrated that the mutation abolishes the
        interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was
        altered.
      explanation: >-
        K69R abolishes alpha-actinin-2 binding in cell culture, which is the variant-to-binding
        step for this allele.
    - reference: PMID:20044516
      reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with
        wild-type MLP.
      explanation: >-
        W4R weakens telethonin binding in vitro, which is the variant-to-binding step for the
        founding allele.
  - target: Reduced Myocardial MLP Abundance
    causal_link_type: DIRECT
    description: >-
      The W4R allele lowers MLP mRNA and protein in knock-in mouse hearts. In human HCM hearts,
      at least one CSRP3 missense protein appears destabilised. No measurement exists in human
      CMD1M myocardium.
    evidence:
    - reference: PMID:20044516
      reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels
        in hearts of heterozygous and homozygous W4R-MLP knock-in animals.
      explanation: >-
        W4R lowers MLP levels in heterozygous knock-in mouse hearts. This is a mouse finding.
    - reference: PMID:18505755
      reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: >-
        Our functional data from both in vitro and in vivo analyses suggest that at least one of
        MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a
        CSRP3 missense mutation.
      explanation: >-
        Human myocardial evidence that a CSRP3 missense protein can be destabilised. INDIRECT
        because the patients had hypertrophic cardiomyopathy, not CMD1M.
- name: Loss of MLP Binding to Telethonin and Alpha-Actinin-2
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    MLP binds telethonin (T-cap), which in turn binds the N-terminus of titin, and
    alpha-actinin-2, the main Z-disc actin cross-linker. W4R weakens the telethonin interaction
    and K69R abolishes the alpha-actinin-2 interaction. In the founding study, telethonin was
    lost from the Z-disc in a subset of MLP-null mouse cardiomyocytes and in myocardial
    biopsies from W4R carriers. A dilated-cardiomyopathy variant in the partner, ACTN2 Q9R, also
    disrupts MLP binding, which supports the view that this complex is the relevant one.
  genes:
  - preferred_term: CSRP3
    term:
      id: hgnc:2472
      label: CSRP3
  molecular_functions:
  - preferred_term: Telethonin binding
    term:
      id: GO:0031433
      label: telethonin binding
    modifier: DECREASED
  - preferred_term: Muscle alpha-actinin binding
    term:
      id: GO:0051371
      label: muscle alpha-actinin binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:12507422
    reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein.
    explanation: >-
      Establishes the MLP-telethonin interaction that the W4R allele disrupts.
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Analysis in cell culture systems demonstrated that the mutation abolishes the
      interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was
      altered.
    explanation: >-
      K69R abolishes alpha-actinin-2 binding and changes where MLP sits in the cell.
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In this regard, we observed loss of telethonin at the Z-disc in a subset of MLP−/−
      cardiomyocytes as well as in myocardial biopsies from patients carrying the W4R-MLP
      mutation, which is supported by our finding that W4R-MLP binds with less affinity to
      telethonin [26, 27].
    explanation: >-
      The review's summary of the founding group's own work, including the only human
      myocardial observation of the binding defect: telethonin lost from the Z-disc in biopsies
      from W4R carriers. Graded HUMAN_CLINICAL for that biopsy finding. The MLP-null part of the
      sentence is mouse data.
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: >-
      This mutation also disrupted the interaction with MLP and appeared to inhibit
      alpha-actinin function in cultured cells, in respect to the nuclear localization of
      actinin and the initiation of cellular differentiation.
    explanation: >-
      The subject is the ACTN2 Q9R variant found in a dilated-cardiomyopathy patient. The same
      interaction is disrupted from the partner side. INDIRECT because the variant is in ACTN2,
      not CSRP3.
  downstream:
  - target: Defective Cardiomyocyte Stretch Sensing
    causal_link_type: DIRECT
    description: >-
      Loss of the Z-disc MLP/telethonin complex is proposed to disable stretch sensing in the
      cardiomyocyte.
    evidence:
    - reference: PMID:12507422
      reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        We propose that a Z disc MLP/T-cap complex is a key component of the in vivo
        cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to
        human DCM and associated heart failure.
      explanation: >-
        The authors' conclusion, drawn from MLP-deficient mouse heart and cell studies, that the
        MLP/telethonin complex is part of the stretch sensor. The extension to human disease is
        stated as a proposal.
- name: Reduced Myocardial MLP Abundance
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A lower dose of functional MLP in the myocardium. W4R knock-in mice have reduced MLP mRNA
    and protein, and heterozygous MLP+/- mice show that halving MLP is enough to worsen
    remodeling under stress. Whether human CMD1M variants reduce myocardial MLP has not been
    measured. The node is HYPOTHETICAL for that reason.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:20044516
    reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels
      in hearts of heterozygous and homozygous W4R-MLP knock-in animals.
    explanation: >-
      Reduced MLP in W4R knock-in mouse hearts.
  downstream:
  - target: Disrupted Cardiomyocyte Cytoarchitecture
    causal_link_type: DIRECT
    description: >-
      Complete loss of MLP disrupts cardiomyocyte cytoarchitecture in the mouse. Whether a
      partial reduction does the same in human myocardium is not known.
    evidence:
    - reference: PMID:9039266
      reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: >-
        At birth, these hearts were not hypertrophic, but already abnormally soft, with
        cell-autonomous and MLP-sensitive alterations in cytoarchitecture.
      explanation: >-
        Loss of MLP alters cardiomyocyte cytoarchitecture before any hypertrophy appears.
        INDIRECT because this is a complete null in mouse, not a partial reduction in humans.
  - target: Impaired Z-Disc Calcineurin-NFAT Stress Signalling
    causal_link_type: DIRECT
    description: >-
      In heterozygous MLP+/- mice, halving MLP displaces calcineurin from the Z-disc and blunts
      stress-induced NFAT activation.
    evidence:
    - reference: PMID:15665106
      reference_title: "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the
        Z-disk in MLP+/- mice, indicating that MLP is essential for calcineurin anchorage to the
        Z-disk.
      explanation: >-
        Halving MLP in heterozygous mice is enough to displace calcineurin from the Z-disc. This
        is the gene-dose step from reduced MLP to the signalling defect.
  - target: Sarcoplasmic Reticulum Calcium Cycling Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In MLP-null mice, ablating phospholamban rescues the cardiomyopathy. This implicates
      phospholamban-SERCA2a inhibition in disease progression. How loss of MLP produces that
      calcium-cycling defect is not established.
    evidence:
    - reference: PMID:21484537
      reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        phospholamban (PLN) was ablated in MLP−/− animals and, similar to the previous study, a
        complete rescue effect was observed
      explanation: >-
        Confirms that the phospholamban-ablation rescue was done in the MLP-null background,
        which the rescue paper's abstract does not name.
    - reference: PMID:21484537
      reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The stunning improvement of function in these double transgenic mouse models is not
        solely due to improved calcium metabolism because MLP-deficient animals exhibit normal
        or enhanced sacroplasmic reticulum calcium ATPase (SERCA) function [50]
      explanation: >-
        The same review argues against a primary SERCA defect in MLP-null hearts. That is why
        this edge is typed INDIRECT_UNKNOWN_INTERMEDIATES and the target node is HYPOTHETICAL.
        The typo "sacroplasmic" is in the source.
- name: Defective Cardiomyocyte Stretch Sensing
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    MLP-null cardiomyocytes fail to induce brain natriuretic peptide in response to mechanical
    stretch, yet still respond to endothelin-1 or phenylephrine. That pattern places MLP
    upstream in the stretch-specific signalling pathway. The defect has been shown in mouse and
    rat cardiomyocytes and in W4R knock-in cells, not in human CMD1M tissue.
  biological_processes:
  - preferred_term: Detection of muscle stretch
    term:
      id: GO:0035995
      label: detection of muscle stretch
    modifier: DECREASED
  - preferred_term: Cellular response to mechanical stimulus
    term:
      id: GO:0071260
      label: cellular response to mechanical stimulus
    modifier: DECREASED
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:12507422
    reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here, we present biophysical/biochemical studies in muscle LIM protein (MLP) deficient
      cardiac muscle that support a selective role for this Z disc protein in mechanical
      stretch sensing.
    explanation: >-
      Direct evidence, from MLP-deficient cardiac muscle, that MLP takes part in stretch
      sensing.
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      are defective upon mechanical stimulation in brain natriuretic peptide (BNP) induction,
      which is an important indicator of cell stretch, whereas endothelin 1 or phenylephrine
      (PE) were still able to induce BNP expression in these cells
    explanation: >-
      The subject of this sentence in the review is MLP-null isolated cardiomyocytes. It shows
      the defect is specific to stretch: agonist-induced BNP expression is preserved.
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A similar defect in BNP gene expression following stretch in an in vitro cell culture
      system has also been obtained when the W4R-MLP mutation
    explanation: >-
      The sentence continues that the W4R allele was analysed in a knock-in mouse model: cultured
      cardiomyocytes carrying the human allele show the same stretch-specific BNP defect, so the
      allele itself, not only complete MLP loss, impairs stretch sensing. The quote stops before
      the sentence's parenthetical about human carriers, which is cited separately.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of stretch sensing is proposed to leave the myocardium unable to adapt to
      hemodynamic load, ending in chamber dilation. The intermediate steps are not mapped.
    evidence:
    - reference: PMID:12507422
      reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        We propose that a Z disc MLP/T-cap complex is a key component of the in vivo
        cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to
        human DCM and associated heart failure.
      explanation: >-
        The authors connect the stretch-sensor defect to dilated cardiomyopathy, but they frame
        it as a proposal. Hence the INDIRECT_UNKNOWN_INTERMEDIATES link type.
    - reference: PMID:21484537
      reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        MLP is dismissible during embryonic development but essential for adaptation of the
        heart to increased hemodynamic demands after birth, where MLP-deficient animals begin
        to develop heart failure
      explanation: >-
        Disease in MLP-deficient mice begins after birth, when hemodynamic load rises. This fits
        a failure to adapt to load.
- name: Impaired Z-Disc Calcineurin-NFAT Stress Signalling
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    MLP anchors calcineurin at the Z-disc. When MLP is reduced, calcineurin is displaced and
    stress-induced calcineurin-NFAT activation is blunted. Calcineurin is protective in this
    setting: deleting calcineurin A-beta in MLP-null mice worsens the cardiomyopathy, and
    activated calcineurin improves it. All evidence for this node is from mice and cultured
    cardiomyocytes.
  biological_processes:
  - preferred_term: Calcineurin-NFAT signaling cascade
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    modifier: DECREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:15665106
    reference_title: "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our study reveals a link between the stress sensor MLP and the calcineurin-NFAT pathway
      at the sarcomeric Z-disk in cardiomyocytes and indicates that reduced MLP-calcineurin
      signaling predisposes to adverse remodeling after MI.
    explanation: >-
      Links MLP to calcineurin-NFAT signalling at the Z-disc.
  - reference: PMID:19854199
    reference_title: "Calcineurin protects the heart in a murine model of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Antithetically, mild overexpression of activated calcineurin in the mouse heart improved
      function and adverse remodeling in MLP knock-out mice.
    explanation: >-
      Restoring calcineurin activity improves MLP-null cardiomyopathy, so loss of calcineurin
      signalling contributes to the phenotype.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      With reduced MLP-calcineurin signalling, the ventricle remodels badly under stress and
      dilates.
    evidence:
    - reference: PMID:15665106
      reference_title: "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        After MI, however, MLP+/- mice displayed more pronounced LV dilatation and systolic
        dysfunction and decreased survival compared with WT mice, indicating that reduced MLP
        levels predispose to adverse LV remodeling.
      explanation: >-
        In heterozygous mice, reduced MLP leads to greater LV dilatation and systolic dysfunction
        after infarction. The sham-operated heterozygotes were normal, so the effect appears
        only under stress.
    - reference: PMID:19854199
      reference_title: "Calcineurin protects the heart in a murine model of dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        The MLP/calcineurin A beta double knock-out mice that survived until adulthood showed
        reduced left ventricular function, enhanced apoptotic and necrotic cardiomyocyte death
        and augmented myocardial fibrosis compared to various control groups.
      explanation: >-
        Removing calcineurin A-beta from MLP-null mice worsens left ventricular function, which
        supports the step from lost calcineurin signalling to ventricular failure.
- name: Disrupted Cardiomyocyte Cytoarchitecture
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Without MLP, cardiomyocyte cytoarchitecture is disorganised at the ultrastructural level,
    and newborn hearts are abnormally soft before any hypertrophy develops. MLP deficiency also
    causes a defect in passive elasticity, which precedes global heart failure. These findings
    come from the knockout mouse.
  biological_processes:
  - preferred_term: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:9039266
    reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture.
    explanation: >-
      The ultrastructural lesion in MLP-null hearts.
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Another important aspect was the significant defect in passive elasticity under MLP
      deficiency, which is probably responsible for the diastolic dysfunction observed in these
      animals before they develop global heart failure.
    explanation: >-
      A mechanical correlate of the structural lesion, present before heart failure.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      Disorganised cytoarchitecture is the knockout paper's stated route to dilated
      cardiomyopathy.
    evidence:
    - reference: PMID:9039266
      reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Thus, MLP promotes proper cardiomyocyte cytoarchitecture, whose perturbation can lead to
        dilated cardiomyopathy.
      explanation: >-
        The authors' causal conclusion from the knockout mouse, linking cytoarchitectural
        disruption to dilated cardiomyopathy.
- name: Sarcoplasmic Reticulum Calcium Cycling Defect
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Chronic inhibition of SERCA2a by phospholamban has been proposed as the calcium-cycling
    defect that drives chamber dilation in the MLP-null mouse, because ablating phospholamban
    rescues the phenotype. MLP-null hearts, however, are reported to have normal or enhanced
    SERCA function. The rescue may therefore work by bypassing the MLP lesion rather than by
    correcting it. MLP-null human stem-cell cardiomyocytes also show abnormal calcium handling,
    but they model hypertrophic rather than dilated disease. The node is HYPOTHETICAL for
    CMD1M.
  biological_processes:
  - preferred_term: Sarcoplasmic reticulum calcium ion transport
    term:
      id: GO:0070296
      label: sarcoplasmic reticulum calcium ion transport
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:10555147
    reference_title: "Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor,
      phospholamban, rescued the spectrum of phenotypes that resemble human heart failure.
    explanation: >-
      Phospholamban ablation rescues the mouse dilated-cardiomyopathy model. A review confirms
      that the model was the MLP-null mouse (see the incoming edge).
  - reference: PMID:31406109
    reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: >-
      Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of
      HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a
      central mechanism for pathogenesis of MLP deficiency.
    explanation: >-
      Human-cell evidence that MLP loss disturbs calcium homeostasis. INDIRECT because the
      phenotype is HCM-like rather than dilated, and the cells are a full knockout rather than a
      patient allele.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      In the mouse model, progressive chamber dilation depends on the SR calcium-cycling
      defect.
    evidence:
    - reference: PMID:10555147
      reference_title: "Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Via complementation of a genetically based mouse model of dilated cardiomyopathy, we
        now provide evidence that progressive chamber dilation and heart failure are dependent
        on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum.
      explanation: >-
        The rescue study's conclusion that chamber dilation depends on the SR calcium-cycling
        defect, shown in the MLP-null mouse.
- name: Left Ventricular Dilation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  mechanism_confidence: PROVISIONAL
  description: >-
    The defining remodeling of dilated cardiomyopathy: an enlarged left ventricle with falling
    systolic function. In the MLP-null mouse it develops after birth and is accompanied by
    hypertrophy. Human CMD1M reports describe dilated cardiomyopathy without further structural
    detail in their abstracts.
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:9039266
    reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after
      birth.
    explanation: >-
      The ventricular phenotype of the MLP-null mouse.
  - reference: PMID:12507422
    reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results
      in a marked defect in T-cap interaction/localization.
    explanation: >-
      The human dilated-cardiomyopathy phenotype that the founding CSRP3 allele was reported
      with.
  downstream:
  - target: Heart Failure
    causal_link_type: DIRECT
    description: >-
      Progressive dilation and systolic dysfunction lead to heart failure.
    evidence:
    - reference: PMID:9039266
      reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        In vivo analysis revealed that MLP-deficient mice reproduce the morphological and
        clinical picture of dilated cardiomyopathy and heart failure in humans, providing the
        first model for this condition in a genetically manipulatable organism.
      explanation: >-
        In the knockout mouse, dilated cardiomyopathy progresses to heart failure.
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      Left ventricular dilation with systolic dysfunction is the clinical phenotype of dilated
      cardiomyopathy.
    evidence:
    - reference: PMID:12507422
      reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results
        in a marked defect in T-cap interaction/localization.
      explanation: >-
        The founding CSRP3 allele was reported in patients with the clinical dilated
        cardiomyopathy phenotype.
- name: Heart Failure
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  mechanism_confidence: PROVISIONAL
  description: >-
    Clinical pump failure from the dilated, poorly contracting ventricle. It is the reported
    outcome in the MLP-null mouse, and W4R carriers have been described with cardiomyopathy and
    heart failure.
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the W4R-MLP mutation, observed in human individuals affected by cardiomyopathy and heart
      failure
    directness: INDIRECT
    explanation: >-
      The review's description of the human W4R carriers, which includes heart failure.
      INDIRECT because the phrase is a parenthetical inside a sentence about a knock-in mouse
      experiment, and it says "cardiomyopathy" without specifying dilated cardiomyopathy.
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
    description: >-
      The organism-level failure appears clinically as congestive heart failure.
    evidence:
    - reference: PMID:21484537
      reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        the W4R-MLP mutation, observed in human individuals affected by cardiomyopathy and heart
        failure
      explanation: >-
        Clinical heart failure reported in human W4R carriers. INDIRECT for the reasons given on
        the Heart Failure node.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular dilation with systolic dysfunction. It is the defining feature of the
    locus and is present in every reported proband by definition.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  diagnostic: true
  evidence:
  - reference: PMID:12507422
    reference_title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results
      in a marked defect in T-cap interaction/localization.
    explanation: >-
      Dilated cardiomyopathy is the phenotype the founding CSRP3 allele was reported with.
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified a patient with DCM and EFE, having a mutation in MLP with the residue
      lysine 69 substituted by arginine (K69R).
    explanation: >-
      Dilated cardiomyopathy in the K69R patient.
  notes: >-
    No frequency band is assigned. Dilated cardiomyopathy is the ascertainment criterion for
    every reported case, so a frequency would be circular.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Heart failure following the ventricular dilation, reported in human W4R carriers and in the
    knockout mouse.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the W4R-MLP mutation, observed in human individuals affected by cardiomyopathy and heart
      failure
    directness: INDIRECT
    explanation: >-
      Heart failure in human W4R carriers, as summarised by the group that reported the allele.
      INDIRECT because the phrase is a parenthetical inside a sentence about a knock-in mouse
      experiment, and it says "cardiomyopathy" without specifying dilated cardiomyopathy.
  notes: >-
    No frequency is assigned because the cached sources give no denominator for heart failure
    among CSRP3 dilated-cardiomyopathy carriers.
- name: Endocardial Fibroelastosis
  category: Cardiovascular
  description: >-
    Fibroelastic thickening of the endocardium, reported together with dilated cardiomyopathy in
    the single K69R patient.
  phenotype_term:
    preferred_term: Endocardial fibroelastosis
    term:
      id: HP:0001706
      label: Endocardial fibroelastosis
  evidence:
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified a patient with DCM and EFE, having a mutation in MLP with the residue
      lysine 69 substituted by arginine (K69R).
    explanation: >-
      Endocardial fibroelastosis in the K69R patient.
  notes: >-
    Seen in one patient. No frequency is assigned. The phenotype is left unconnected in the
    pathograph because no cited source proposes a mechanism linking MLP to endocardial
    fibroelastosis.
genetic:
- name: CSRP3
  gene_term:
    preferred_term: CSRP3
    term:
      id: hgnc:2472
      label: CSRP3
  variant_origin: GERMLINE
  association: >-
    Heterozygous CSRP3 missense variants reported in dilated cardiomyopathy (W4R, K69R and
    single variants from cohort screens). The relationship is classified Limited by ClinGen.
    relationship_type is left unset because CAUSATIVE is reserved for Definitive or Strong
    relationships.
  gene_disease_validity:
  - validity_classification: LIMITED
    classified_by: CLINGEN
    external_id: CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z
    evidence:
    - reference: CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z
      reference_title: "CSRP3 / dilated cardiomyopathy 1M (Limited)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CSRP3 | HGNC:2472 | dilated cardiomyopathy 1M | MONDO:0011840 | AD | Limited"
      explanation: >-
        ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies CSRP3 for this
        exact MONDO term as Limited, autosomal dominant (SOP10, 2026-03-04).
  variants:
  - name: CSRP3 p.Trp4Arg (W4R)
    description: >-
      The founding allele, c.10T>C in exon 2 according to the 2010 knock-in paper. It weakens
      telethonin binding and lowers MLP levels in knock-in mice. It is carried by up to 1% of
      people of European ancestry and did not segregate with dilated cardiomyopathy in the one
      family where segregation was tested. On current evidence it is best read as a common
      low-penetrance or benign variant, not a monogenic cause of this disease.
  - name: CSRP3 p.Lys69Arg (K69R)
    description: >-
      Reported in one patient with dilated cardiomyopathy and endocardial fibroelastosis. It sits
      in a conserved region next to the first LIM domain and abolishes alpha-actinin-2 binding in
      cell culture. Segregation is not reported in the abstract.
  - name: CSRP3 p.Gly72Arg (G72R)
    description: >-
      The single CSRP3 variant among 313 dilated-cardiomyopathy probands in Hershberger 2008.
      It replaces a conserved residue and was judged possibly disease-causing.
  - name: CSRP3 p.Glu191Lys (E191K)
    description: >-
      NM_003476.5:c.571G>A, heterozygous, in one of 31 dilated-cardiomyopathy subjects in a Thai
      clinical series (Trachoo 2022), classified as a variant of uncertain significance.
  evidence:
  - reference: CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z
    reference_title: "CSRP3 / dilated cardiomyopathy 1M (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSRP3 | HGNC:2472 | dilated cardiomyopathy 1M | MONDO:0011840 | AD | Limited"
    explanation: >-
      The current expert-panel classification for this gene and this disease.
  - reference: PMID:20044516
    reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data
      suggest that (W4R-MLP) might contribute significantly to human cardiovascular disease.
    explanation: >-
      States the population frequency of W4R. The authors read it as a common contributor to
      cardiovascular disease. That frequency also makes W4R implausible as a penetrant monogenic
      cause of a rare cardiomyopathy.
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Previous studies have shown an association between CSRP3 missense mutations and either
      dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide
      comprehensive genetic evidence for a causative role of CSRP3 mutations.
    explanation: >-
      The 2008 linkage study that confirmed CSRP3 as an HCM gene judged the earlier
      dilated-cardiomyopathy reports to lack comprehensive genetic evidence for causation. The parent
      Dilated_Cardiomyopathy entry cites the same sentence.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      CSRP3 945 60647 0.00029 1.10 (0.35–3.45) 0.09 (0.00–0.71) 0.00070 2.92 (0.39–21.6)
      0.66 (0.00–0.95)
    explanation: >-
      No detectable excess of rare CSRP3 variants in 945 dilated-cardiomyopathy cases compared
      with ExAC (non-truncating OR 1.10, 95% CI 0.35-3.45); a modest effect is not excluded.
  notes: >-
    Gene-disease validity. The ClinGen record
    CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z classifies CSRP3
    for dilated cardiomyopathy 1M (MONDO:0011840, this entry's disease_term) as Limited,
    autosomal dominant, SOP10, dated 2026-03-04. The same assertion is the CSRP3
    dilated-cardiomyopathy row in the committed ClinGen ingest table
    (kb/genes/ingest/clingen_gene_validity.tsv); the only other CSRP3 row there is the
    hypertrophic-cardiomyopathy assertion. The committed cache/clingen/gene_validity.csv
    holds an earlier record of the same assertion (2025-05-30) for the umbrella term dilated
    cardiomyopathy (MONDO:0005021), classified No Known Disease Relationship; the 2026-03-04
    record for MONDO:0011840 is the current one. The deep-research report cites a GenCC summary giving
    "no known disease relationship" for CSRP3 and dilated cardiomyopathy, which conflicts with
    the current ClinGen tier; this entry follows ClinGen. Because CSRP3 has a ClinGen rating
    below Strong for this disease, relationship_type is left unset, as in the sibling CMD1
    entries.

    The CSRP3 hypertrophic-cardiomyopathy assertion (Definitive, semi-dominant,
    MONDO:0005045) is a different disease and is not copied here. It is curated on the
    Hypertrophic_Cardiomyopathy entry.

    The cached ClinGen record is the CSV row only. The report-page narrative, which scores the
    individual dilated-cardiomyopathy variants, was not cached, so no ClinGen variant scores are
    quoted here.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: UNKNOWN
  description: >-
    ClinGen curated the relationship under autosomal dominant inheritance. Zygosity is stated
    explicitly only for the Trachoo E191K subject (heterozygous); the other reports do not
    state zygosity in the cited text. Penetrance cannot be estimated. No segregating
    dilated-cardiomyopathy family is described in the cached sources, and the founding allele W4R is
    common in the population and failed to segregate in the one family where it was tested.
  evidence:
  - reference: CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z
    reference_title: "CSRP3 / dilated cardiomyopathy 1M (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSRP3 | HGNC:2472 | dilated cardiomyopathy 1M | MONDO:0011840 | AD | Limited"
    explanation: >-
      Records the mode of inheritance (AD) that the expert panel curated.
diagnosis:
- name: Clinical Evaluation for Nonsyndromic Dilated Cardiomyopathy
  description: >-
    The phenotype is established clinically, with imaging showing a dilated, poorly contracting
    left ventricle after ischaemic, valvular and other acquired causes have been excluded. No
    imaging, biopsy or biomarker feature specific to CSRP3 has been reported.
  evidence:
  - reference: PMID:20301486
    reference_title: "Dilated Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews overview sets out how to evaluate a dilated-cardiomyopathy proband. It is
      INDIRECT because it covers the disease class, not CSRP3.
- name: Multigene Cardiomyopathy Panel Testing
  description: >-
    CSRP3 appears on many dilated-cardiomyopathy panels. At a Limited classification, a CSRP3
    variant found in a dilated-cardiomyopathy proband should not be reported as a molecular
    diagnosis on its own. W4R in particular is too common to be interpreted as causal. Testing
    is most useful for finding a variant in a high-evidence gene.
  evidence:
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      We recommend that high-evidence DCM genes be used for clinical practice and that caution
      be exercised in the interpretation of variants in variable-evidence DCM genes.
    explanation: >-
      The expert recommendation that applies to a Limited gene such as CSRP3. INDIRECT because
      the abstract does not name CSRP3.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We found that in some genes previously reported as important causes of a given
      cardiomyopathy, rare variation is not clinically informative because there is an
      unacceptably high likelihood of false-positive interpretation.
    explanation: >-
      The study that found no CSRP3 enrichment in dilated cardiomyopathy concludes that rare
      variants in genes like this one are prone to false-positive interpretation.
differential_diagnoses:
- name: Hypertrophic Cardiomyopathy 12
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 12
    term:
      id: MONDO:0012804
      label: hypertrophic cardiomyopathy 12
  description: >-
    The allelic CSRP3 disorder (CMH12), and the better-established one. CSRP3 missense variants
    segregate with hypertrophic cardiomyopathy in several families, and ClinGen rates CSRP3 for
    hypertrophic cardiomyopathy as Definitive with semi-dominant inheritance. Biallelic CSRP3
    truncating variants have been reported in adult hypertrophic cardiomyopathy. A CSRP3
    carrier with a dilated ventricle needs hypertrophic cardiomyopathy with later dilation
    considered. dismech curates CSRP3 hypertrophic disease on the Hypertrophic_Cardiomyopathy
    entry. CMH12 itself is still a stub.
  distinguishing_features:
  - >-
    Unexplained left ventricular hypertrophy rather than primary dilation. In the HCM carriers
    of the 2008 study there was also evidence of mild skeletal muscle disease.
  evidence:
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We used linkage analysis and identified a CSRP3 missense mutation in a large German family
      affected by HCM. We confirmed CSRP3 as an HCM disease gene.
    explanation: >-
      Linkage evidence establishing CSRP3 as a hypertrophic-cardiomyopathy gene.
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other
      families.
    explanation: >-
      Segregation in four more HCM families, in contrast with no segregating CMD1M family.
  - reference: PMID:18505755
    reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We also present evidence for mild skeletal muscle disease in affected persons.
    explanation: >-
      Mild skeletal muscle disease in HCM carriers. It is not reported for CMD1M, so it is
      recorded here rather than as a CMD1M phenotype.
  - reference: CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z
    reference_title: "CSRP3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSRP3 | HGNC:2472 | hypertrophic cardiomyopathy | MONDO:0005045 | SD | Definitive"
    explanation: >-
      The ClinGen hypertrophic-cardiomyopathy assertion, quoted here only to contrast it with the
      Limited dilated-cardiomyopathy assertion. It is the same row the Hypertrophic_Cardiomyopathy
      entry cites.
  - reference: PMID:38666070
    reference_title: "Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Conversely, biallelic PTVs in CSRP3 are seemingly associated with HCM in adults (based on
      six reported cases)
    explanation: >-
      Biallelic CSRP3 truncating variants produce hypertrophic, not dilated, disease (six
      reported cases).
- name: Dilated Cardiomyopathy 1AA
  disease_term:
    preferred_term: dilated cardiomyopathy 1AA
    term:
      id: MONDO:0012808
      label: dilated cardiomyopathy 1AA
  description: >-
    ACTN2-related dilated cardiomyopathy. Alpha-actinin-2 is the Z-disc partner whose binding
    K69R abolishes, and a dilated-cardiomyopathy ACTN2 variant (Q9R) reported in the same 2003
    screen disrupts MLP binding from the other side. The two cannot be told apart clinically;
    only sequencing separates them.
  distinguishing_features:
  - >-
    The variant is in ACTN2 (alpha-actinin-2) rather than CSRP3.
  evidence:
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2.
    explanation: >-
      An ACTN2 variant in dilated cardiomyopathy, found in the same screen as K69R.
- name: Dilated Cardiomyopathy
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  description: >-
    Dilated cardiomyopathy from other genes or acquired causes. Because CSRP3 is a Limited gene
    and the founding allele is common, most CSRP3 carriers with dilated cardiomyopathy are
    better explained by a variant in a high-evidence gene or by an acquired cause. Ischaemic,
    toxic, inflammatory and peripartum dilated cardiomyopathy should be excluded clinically.
  distinguishing_features:
  - >-
    A pathogenic variant in a Definitive or Strong dilated-cardiomyopathy gene, or an identified
    acquired cause.
  evidence:
  - reference: PMID:19412328
    reference_title: "Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Mutations of these six genes each account for a small fraction of the genetic cause of
      FDC/IDC.
    explanation: >-
      CSRP3 is one of several genes that each explain only a small fraction of dilated
      cardiomyopathy.
treatments:
- name: Guideline-Directed Heart Failure Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Management follows standard guideline-directed therapy for dilated cardiomyopathy and heart
    failure with reduced ejection fraction. No CSRP3-specific therapy or trial exists.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Heart Failure
    description: >-
      Acts on the heart-failure end of the chain, not on the MLP lesion.
  evidence:
  - reference: PMID:35379503
    reference_title: "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      The recommendations present an evidence-based approach to managing patients with heart
      failure, with the intent to improve quality of care and align with patients' interests.
    explanation: >-
      The guideline that management follows. INDIRECT because it is written for heart failure in
      general and does not mention CSRP3.
- name: Cardiac Transplantation
  therapeutic_modality: SURGERY
  description: >-
    The usual option for refractory end-stage dilated cardiomyopathy.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Heart Failure
    description: >-
      Replaces the failing organ. It does not address the mechanism.
  notes: >-
    No cited source reports transplantation in a CSRP3 dilated-cardiomyopathy patient. It is
    listed as standard management for end-stage dilated cardiomyopathy and carries no
    CSRP3-specific evidence.
- name: Genetic Counseling
  therapeutic_modality: OTHER
  description: >-
    Counseling should explain that the CSRP3 dilated-cardiomyopathy relationship is Limited, so
    a CSRP3 variant alone does not justify predictive testing of relatives. Clinical
    (echocardiographic) screening of first-degree relatives follows general familial
    dilated-cardiomyopathy practice.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      We recommend that high-evidence DCM genes be used for clinical practice and that caution
      be exercised in the interpretation of variants in variable-evidence DCM genes.
    explanation: >-
      The basis for advising caution about acting on a CSRP3 result. INDIRECT because the
      abstract does not name CSRP3.
animal_models:
- name: Csrp3 (Mlp) knockout mouse
  species: Mouse
  genotype: Csrp3-/- (MLP-/-), homozygous null
  publication: PMID:9039266
  description: >-
    The classic MLP-deficient mouse, the first genetically engineered mouse model of dilated
    cardiomyopathy. Hearts are abnormally soft at birth, with disrupted cardiomyocyte
    cytoarchitecture. After birth the mice develop dilated cardiomyopathy with hypertrophy and
    heart failure.
  modeled_mechanisms:
  - target: Disrupted Cardiomyocyte Cytoarchitecture
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The structural lesion that the cytoarchitecture node is built on.
    limitations: >-
      Complete loss of MLP, whereas human CMD1M carriers are heterozygous for missense alleles
      whose effect on MLP dose has not been measured in human myocardium.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        A homozygous null does not represent a heterozygous missense variant. In humans,
        biallelic CSRP3 truncation gives hypertrophic rather than dilated cardiomyopathy.
    evidence:
    - reference: PMID:9039266
      reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture.
      explanation: >-
        The cytoarchitectural lesion in the model.
  - target: Left Ventricular Dilation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Produces dilated cardiomyopathy and heart failure that resemble the human clinical
      picture.
    limitations: >-
      The dilation comes with hypertrophy, and the genotype is a complete null. The model shows
      that loss of MLP can cause dilated cardiomyopathy in mice. It does not show that
      heterozygous human CSRP3 variants do.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        In humans, complete or near-complete loss of MLP is associated with hypertrophic, not
        dilated, cardiomyopathy. The direction of remodeling therefore differs between mouse
        and human.
    evidence:
    - reference: PMID:9039266
      reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after
        birth.
      explanation: >-
        Dilated cardiomyopathy and heart failure in the model, with hypertrophy.
  evidence:
  - reference: PMID:9039266
    reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In vivo analysis revealed that MLP-deficient mice reproduce the morphological and clinical
      picture of dilated cardiomyopathy and heart failure in humans, providing the first model
      for this condition in a genetically manipulatable organism.
    explanation: >-
      The authors' statement of the model's fidelity to human dilated cardiomyopathy.
- name: Heterozygous Csrp3 (MLP+/-) mouse after myocardial infarction
  species: Mouse
  genotype: Csrp3+/- (MLP+/-), heterozygous null, with experimental myocardial infarction
  publication: PMID:15665106
  description: >-
    Mice with half the normal MLP dose. Their hearts are normal at baseline but dilate more,
    and fail more, after myocardial infarction. Calcineurin is displaced from the Z-disc. This
    is the closest mouse analogue to a heterozygous human state.
  modeled_mechanisms:
  - target: Impaired Z-Disc Calcineurin-NFAT Stress Signalling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Shows calcineurin displacement and blunted NFAT activation with a reduced MLP dose.
    limitations: >-
      The phenotype appears only after an infarction. Heterozygous null is not the same as a
      human missense allele.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Myocardial infarction is the stressor here. No comparable stressor is documented in
        human CMD1M.
    evidence:
    - reference: PMID:15665106
      reference_title: "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the
        Z-disk in MLP+/- mice, indicating that MLP is essential for calcineurin anchorage to the
        Z-disk.
      explanation: >-
        The signalling readout in the heterozygous model.
  evidence:
  - reference: PMID:15665106
    reference_title: "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      LV dimensions and function were similar in sham-operated WT and MLP+/- mice.
    explanation: >-
      Heterozygous mice have no baseline phenotype. This is the main limitation of the model as
      a stand-alone CMD1M model.
- name: MLP-null and phospholamban-null double knockout mouse
  species: Mouse
  genotype: Csrp3-/- Pln-/- (MLP-/- PLN-/-)
  publication: PMID:10555147
  description: >-
    The MLP-null mouse crossed onto a phospholamban-null background. Removing phospholamban
    rescues the dilated-cardiomyopathy and heart-failure phenotype.
  modeled_mechanisms:
  - target: Sarcoplasmic Reticulum Calcium Cycling Defect
    relationship: RESCUES
    fidelity: LOW
    description: >-
      Relieving SERCA2a inhibition by removing phospholamban rescues the MLP-null
      cardiomyopathy.
    limitations: >-
      A rescue does not show that the defect it corrects is the primary lesion. MLP-null hearts
      are reported to have normal or enhanced SERCA function, so the rescue may act around the
      MLP defect rather than reversing it.
    divergences:
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: >-
        The model assumes that the rescued calcium-cycling defect causes the MLP phenotype. Later
        work on SERCA function in MLP-null hearts disputes this.
    evidence:
    - reference: PMID:10555147
      reference_title: "Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a)
        inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart
        failure.
      explanation: >-
        The rescue result.
    - reference: PMID:21484537
      reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The stunning improvement of function in these double transgenic mouse models is not
        solely due to improved calcium metabolism because MLP-deficient animals exhibit normal
        or enhanced sacroplasmic reticulum calcium ATPase (SERCA) function [50]
      explanation: >-
        Argues against reading the rescue as proof of a primary SERCA defect.
  evidence:
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      phospholamban (PLN) was ablated in MLP−/− animals and, similar to the previous study, a
      complete rescue effect was observed
    explanation: >-
      Confirms that the MLP-null mouse was the background for the phospholamban rescue.
- name: Mlp W4R knock-in mouse
  species: Mouse
  genotype: Mlp(W4R/+) and Mlp(W4R/W4R) knock-in
  publication: PMID:20044516
  description: >-
    Knock-in of the founding CMD1M allele. Heterozygous and homozygous mice develop age- and
    dose-dependent hypertrophic cardiomyopathy and heart failure, lose almost all contractile
    reserve under catecholamine stress, and have reduced MLP and weaker telethonin binding. Some
    skeletal muscle pathology is also present.
  modeled_mechanisms:
  - target: Reduced Myocardial MLP Abundance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Carries the human allele and lowers MLP in the heart.
    limitations: >-
      This is a mouse measurement. MLP levels have not been measured in human W4R myocardium.
    evidence:
    - reference: PMID:20044516
      reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels
        in hearts of heterozygous and homozygous W4R-MLP knock-in animals.
      explanation: >-
        Reduced MLP in knock-in hearts.
  - target: Left Ventricular Dilation and Systolic Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The founding dilated-cardiomyopathy allele produces hypertrophic, not dilated,
      cardiomyopathy in the mouse.
    limitations: >-
      The opposite remodeling direction from the human entity this allele defined.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: INVALIDATING
      description: >-
        As a model of dilated remodeling it fails, because the knock-in develops a hypertrophic
        phenotype.
    evidence:
    - reference: PMID:20044516
      reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and
        Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent
        hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost
        complete loss of contractile reserve under catecholamine induced stress.
      explanation: >-
        The knock-in phenotype is hypertrophic cardiomyopathy.
  evidence:
  - reference: PMID:20044516
    reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      These alterations may contribute to an increased nuclear localization of W4R-MLP, which
      was observed by immunohistochemistry.
    explanation: >-
      A further cellular phenotype of the knock-in: more of the mutant protein is found in the
      nucleus.
discussions:
- discussion_id: cmd1m_entity_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is CMD1M a real Mendelian dilated cardiomyopathy, or a locus built on a common variant and
    a few unsegregated probands?
  attaches_to:
  - genetic#CSRP3
  - disease#Dilated Cardiomyopathy 1M
  rationale: >-
    The human case rests on W4R (common, and non-segregating in one family), K69R (one patient)
    and single probands from cohort screens. No segregating dilated-cardiomyopathy pedigree is
    described in the cached sources, and a 945-case burden comparison found no excess of rare
    CSRP3 variants. ClinGen's Limited rating means the relationship has not been ruled out, and
    MLP biology makes dilated cardiomyopathy plausible. The gap would close with segregation of
    a rare CSRP3 variant in a dilated-cardiomyopathy family, or a burden signal in a large
    cohort.
  evidence:
  - reference: PMID:14567970
    reference_title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In another individual with DCM, a W4R mutation was identified. However, this mutation did
      not segregate with disease in this family.
    explanation: >-
      The founding allele failed to segregate.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      CSRP3 945 60647 0.00029 1.10 (0.35–3.45) 0.09 (0.00–0.71) 0.00070 2.92 (0.39–21.6)
      0.66 (0.00–0.95)
    explanation: >-
      No case excess for CSRP3 in dilated cardiomyopathy.
  - reference: CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z
    reference_title: "CSRP3 / dilated cardiomyopathy 1M (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSRP3 | HGNC:2472 | dilated cardiomyopathy 1M | MONDO:0011840 | AD | Limited"
    explanation: >-
      The expert panel still rates the relationship Limited, not Disputed.
- discussion_id: cmd1m_mouse_dilated_human_hypertrophic
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does loss of MLP give dilated cardiomyopathy in the knockout mouse but mainly
    hypertrophic cardiomyopathy in humans, in the W4R knock-in mouse and in human stem-cell
    cardiomyocytes?
  attaches_to:
  - animal_models#Csrp3 (Mlp) knockout mouse
  - pathophysiology#Left Ventricular Dilation and Systolic Dysfunction
  rationale: >-
    Most of the mechanistic chain in this entry comes from the MLP-null mouse. In humans, CSRP3
    is a Definitive hypertrophic-cardiomyopathy gene, and biallelic truncating variants give
    adult hypertrophic cardiomyopathy. Knock-in of the founding dilated allele gives hypertrophic
    cardiomyopathy in mice, and MLP-null human ESC-derived cardiomyocytes develop hypertrophic
    features. The MLP-null mouse itself has hypertrophy along with dilation. So the dilated
    outcome may reflect mouse strain, complete null dose, or a late dilated phase of a
    hypertrophic process, rather than a distinct dilated mechanism.
  evidence:
  - reference: PMID:20044516
    reference_title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and
      Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent
      hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost
      complete loss of contractile reserve under catecholamine induced stress.
    explanation: >-
      The founding dilated allele gives hypertrophic cardiomyopathy in mice.
  - reference: PMID:31406109
    reference_title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after
      differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric
      ultrastructure.
    explanation: >-
      Human MLP-null cardiomyocytes take on hypertrophic features.
  - reference: PMID:38666070
    reference_title: "Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Conversely, biallelic PTVs in CSRP3 are seemingly associated with HCM in adults (based on
      six reported cases)
    explanation: >-
      Near-complete human loss of CSRP3 gives hypertrophic cardiomyopathy, unlike the knockout
      mouse.
  - reference: PMID:9039266
    reference_title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after
      birth.
    explanation: >-
      Even the knockout mouse shows hypertrophy alongside dilation.
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      MLP deficiency leads to myocardial hypertrophy followed by a dilated cardiomyopathy and
      heart failure phenotype
    explanation: >-
      The review describes the knockout course as hypertrophy first and dilation later, which
      fits the reading that the dilated outcome is a late phase of a hypertrophic process.
- discussion_id: cmd1m_calcium_vs_mechanosensing
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is the phospholamban-SERCA2a calcium-cycling defect a primary driver of MLP-deficient
    cardiomyopathy, or does phospholamban ablation rescue it by acting around a primary
    mechanosensing defect?
  attaches_to:
  - pathophysiology#Sarcoplasmic Reticulum Calcium Cycling Defect
  - pathophysiology#Defective Cardiomyocyte Stretch Sensing
  rationale: >-
    The 1999 rescue paper concluded that progressive dilation depends on an SR calcium-cycling
    defect. The MLP group's later review notes that MLP-null hearts have normal or enhanced SERCA
    function. It proposes that the rescue works through mechanosensation, calcium sensitivity or
    passive stiffness instead. Human stem-cell data again point to calcium, but in a hypertrophic
    context. This entry keeps both branches, with the calcium node marked HYPOTHETICAL.
  evidence:
  - reference: PMID:10555147
    reference_title: "Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Via complementation of a genetically based mouse model of dilated cardiomyopathy, we
      now provide evidence that progressive chamber dilation and heart failure are dependent
      on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum.
    explanation: >-
      The calcium-primacy position.
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The stunning improvement of function in these double transgenic mouse models is not
      solely due to improved calcium metabolism because MLP-deficient animals exhibit normal
      or enhanced sacroplasmic reticulum calcium ATPase (SERCA) function [50]
    explanation: >-
      The counter-position.
  - reference: PMID:21484537
    reference_title: "MLP (muscle LIM protein) as a stress sensor in the heart."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Although considerable efforts have been undertaken to unravel the underlying molecular
      mechanisms-how MLP mutations, either in model organisms or in the human setting cause
      these diseases are still unclear.
    explanation: >-
      The field's own statement that the mechanism remains unresolved.
references:
- reference: PMID:12507422
  title: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."
- reference: PMID:14567970
  title: "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis."
- reference: PMID:19412328
  title: "Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy."
- reference: PMID:36166435
  title: "Genomic findings of hypertrophic and dilated cardiomyopathy characterized in a Thai clinical genetics service."
- reference: PMID:18505755
  title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
- reference: PMID:20044516
  title: "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy."
- reference: PMID:27532257
  title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
- reference: PMID:9039266
  title: "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure."
- reference: PMID:10555147
  title: "Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy."
- reference: PMID:15665106
  title: "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc."
- reference: PMID:19854199
  title: "Calcineurin protects the heart in a murine model of dilated cardiomyopathy."
- reference: PMID:21484537
  title: "MLP (muscle LIM protein) as a stress sensor in the heart."
- reference: PMID:31406109
  title: "MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling."
- reference: PMID:38666070
  title: "Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies."
- reference: PMID:33947203
  title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
- reference: PMID:35379503
  title: "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines."
- reference: PMID:20301486
  title: "Dilated Cardiomyopathy Overview."
  tags:
  - GeneReviews
- reference: CGGV:assertion_beaafc90-20ef-4c81-ad8f-cfcf69d269ca-2026-03-04T170000.000Z
  title: "CSRP3 / dilated cardiomyopathy 1M (Limited)"
- reference: CGGV:assertion_012b9b15-798a-46e2-8164-61a829ceeda1-2023-08-09T160000.000Z
  title: "CSRP3 / hypertrophic cardiomyopathy (Definitive)"
notes: >-
  Scope. This entry covers only the dilated designation CMD1M (MONDO:0011840, OMIM 607482,
  provisional). The allelic hypertrophic disorder CMH12 (MONDO:0012804) is better established
  and is handled as a differential. CSRP3 hypertrophic disease is curated on the
  Hypertrophic_Cardiomyopathy entry, which cites the Definitive ClinGen assertion this entry
  quotes only for contrast.

  Consistency with the parent entry. The Dilated_Cardiomyopathy entry leaves CSRP3 off its gene
  panel. ClinGen's Limited assertion is for the numbered term MONDO:0011840, not the umbrella
  term, and is cached with this entry; the earlier umbrella-term record was No Known Disease
  Relationship (see the genetic notes). It does not change the parent entry's judgement, which
  this entry shares: CSRP3's high-evidence relationship is with hypertrophic cardiomyopathy.

  Evidence base. The human dilated-cardiomyopathy counts here come from PMID:12507422,
  PMID:14567970, PMID:19412328 and PMID:36166435 (the last two cached as full text) and the
  Walsh 2017 table (PMID:27532257). Hershberger 2008 names its one CSRP3 allele as G72R.
  Trachoo 2022 prints the gene as "DRSP3" in its abstract; its Table 1 has one CSRP3
  dilated-cardiomyopathy subject, heterozygous for E191K and classified VUS. ClinGen's own scoring of
  individual variants (for example A50T and T179A) is in its report narrative, which is not
  cached, and is not asserted. Zimmerman 2010 (PMID:20474083), which the deep-research report links to two of
  those variants, does not name CSRP3 in its cached abstract and is not cited.

  Mechanism. The chain runs: variant, then loss of partner binding and reduced MLP dose, then
  defective stretch sensing, impaired calcineurin signalling, disrupted cytoarchitecture and a
  contested SR calcium-cycling defect, then left ventricular dilation and heart failure. Almost
  every step downstream of the variant rests on mouse or cell data. The two human data points
  are telethonin loss in W4R-carrier biopsies and CSRP3 protein destabilisation in hypertrophic
  (not dilated) patient hearts. Endocardial fibroelastosis, seen in one patient, is left
  unconnected because no source gives a mechanism. No CMD1M-specific arrhythmia, conduction
  or skeletal-muscle findings appear in the cited sources, which is why only three phenotypes
  are recorded.

  GeneReviews. There is no CMD1M-specific chapter. The disease-level "Dilated Cardiomyopathy
  Overview" (PMID:20301486) is tagged. Its cached record holds only the purpose statement, so
  no phenotype baseline could be mined from it. `just check-genereviews --online` (Bookshelf
  index snapshot 2026-09-10, run 2026-10-08) reports GeneReviews TAGGED (PMID:20301486, NBK1309,
  matched by identity) and StatPearls NO_CHAPTER.

  Deep research was run with the claude_code provider after the falcon provider was unavailable
  (falcon fallback).

📚

References & Deep Research

References

19

PMID:12507422

The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy.