FHOD3

Summary: FHOD3 associates with SQSTM1/p62 in interaction assays.

Reason: PMID:21149568 uses a human heart-library two-hybrid screen, FH2-bait pull-down from transfected COS-1 lysates, and cellular co-immunoprecipitation to support the interaction. CK2 phosphorylation and the acidic insertion affect association. The pull-down is not a purified two-component reconstitution, and binding an autophagy adaptor does not make FHOD3 an adaptor or establish autophagy activity. The explicit ClinGen campaign policy retains this supported generic interaction as non-core, without inventing a more specific molecular function; the default validator advisory remains applicable.

Summary: Cytoplasm is a supported broad location for FHOD3.

Reason: The exact human target path contains the positive cytoplasm IBD at PTN002509352. Cytoplasmic and myofibrillar localization in PMID:21149568 is concordant. Cytoplasm includes cytoskeletal structures, so the term does not restrict FHOD3 to soluble cytosol. Retain this broad context as non-core while the core synthesis records the experimentally observed sarcomere location. This decision does not dispute PAINT's ancestral placement; the position within the sarcomere remains unresolved.

Summary: FHOD3 is associated with the actin/sarcomeric cytoskeleton.

Reason: PTN002509352 is on the verified human FHOD3 path and carries the positive cytoskeleton assertion. The shared broad localization is supported despite the disagreement between PMID:21149568 and PMID:22509354 about the position within sarcomeres. Early nestin observations in rat H9c2 cells are not generalized to every human cardiac product.

Summary: Sarcomere records the experimentally observed cardiac location more informatively.

Reason: The original SL-0090 cytoskeleton mapping remains a valid broad source assertion. Both PMID:21149568 and PMID:22509354 support sarcomeric localization despite disagreeing about the position within it. Replace this electronic annotation with the observed sarcomere location on that empirical basis, while retaining the independently supported broad cytoskeleton IBA. Official QuickGO is_a/part_of ancestry includes myofibril and cytoplasm above sarcomere but does not include cytoskeleton; this is an evidence-based replacement, not a claim of formal ontology-child refinement. Neither a universal location for every human splice product nor a definitive Z-disc assignment is asserted.

Proposed replacements: sarcomere

Summary: FHOD3 organizes actin filaments in the cardiac cytoskeleton.

Reason: The target descends from PTN008701008, which carries this positive IBD. PMID:19706596 combines depletion/rescue in rat cardiomyocytes with mouse FHOD3 assembly-mutant comparisons, linking the actin-associated molecular mechanism to organization. PMID:21149568 adds cellular myofibril recovery experiments with human constructs. These support direct organizational participation. Purified truncated FHOD3 inhibited assembly in the conditions of PMID:19706596; the cellular phenotype is not recast as universal purified nucleation activity.

Summary: The precise Z-disc localization of FHOD3 remains disputed.

Reason: The SL-0314 mapping agrees with the adult-heart Z-disc observations in PMID:21149568, obtained with an antibody against a region shared by the isoforms. PMID:22509354 instead reports sarcomeric doublets away from Z-lines in adult human ventricular tissue and rodent hearts, with distinct antibodies and mouse preadsorption controls. Antibody specificity, fixation, tissue state and experimental context may contribute to the discrepancy; recency alone does not settle it. Retain uncertainty rather than treating either study as definitive or inferring an isoform-specific annotation from the shared-region antibody.

Summary: FHOD3 contributes directly to organizing sarcomeric actin.

Reason: The human leaf lies below the positive PTN002914248 sarcomere-organization IBD. The mouse donor is part of a phylogenetic node judgment rather than a weak pairwise transfer. PMID:19706596 demonstrates rescue by wild-type mouse FHOD3 but not actin-assembly mutants in rat cardiomyocytes; PMID:21149568 supports myofibril maintenance and recovery with complementary human-construct experiments. Disease segregation is not used as the molecular mechanism.

Summary: Actin filament binding is a conserved FHOD3 molecular function.

Reason: The verified target descends from PTN002509352 and its canonical sequence matches the family MSA exactly. The positive actin-filament-binding IBD is concordant with FH2-dependent actin regulation in PMID:19706596 and cellular actin association in PMID:21149568. The former study infers barbed-end association from seeded-elongation behavior of mouse constructs; it is not a direct binding measurement of every human splice product. No target-specific loss of the inherited function is established.

Summary: Activated FHOD3 constructs promote stress-fiber assembly in cellular assays.

Reason: PTN001143929 is on the real target path and supports this inherited actin-organizing capacity. PMID:15966898 describes activated FHOS2 variants in HeLa cells; PMID:19706596 and PMID:22509354 test mouse truncated constructs in that context. Stress fibers are a contextual output rather than the defining cardiac myofibril role. This non-core decision does not reject the ancestral placement or claim a target-specific evolutionary loss.

Summary: FHOD3 actin organization contributes to cardiac myofibril assembly.

Reason: The positive cardiac-myofibril-assembly IBD at PTN002914248 lies on the verified human path. FH2-dependent rescue of sarcomeric organization in PMID:19706596 and actin/myofibril recovery in PMID:21149568 support direct participation through actin organization. The delayed depletion effects in the latter study concern maintenance of existing myofibrils; they are not by themselves evidence for every stage of initial embryonic sarcomerogenesis.