ALPK3 – Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder primarily driven by sarcomeric gene mutations but increasingly linked to non-sarcomeric genes such as ALPK3. Biallelic truncating variants in ALPK3 were first described in severe pediatric-onset HCM with dysmorphic features, establishing a recessive inheritance model ([PMID:28630369]). Subsequent studies identified heterozygous truncating ALPK3 variants (ALPK3tv) as a cause of adult-onset HCM, expanding the phenotypic and inheritance spectrum to an autosomal dominant mechanism ([PMID:34263907]).

Genetic evidence supports autosomal dominant transmission of ALPK3tv in HCM. In a discovery cohort of 770 HCM probands, 12 (1.56%) carried ALPK3tv and 32 of 2047 (1.56%) in a validation cohort (OR 16.17) possessed heterozygous truncating changes, notably c.4689G>A (p.Trp1563Ter) ([PMID:34263907]; [PMID:34526680]). A multicenter cohort of 21 unrelated individuals with heterozygous ALPK3tv further delineated adult-onset presentations ([PMID:39606411]).

Segregation analysis in seven families yielded a combined LOD score of 2.99, confirming co-segregation of ALPK3tv with HCM in autosomal dominant pedigrees ([PMID:34263907]). No significant segregation was observed for ALPK3 variants alone in an oligogenic context, underscoring variable penetrance ([PMID:28223422]).

Phenotypic analyses reveal that heterozygous ALPK3tv carriers present later (mean age ~57 y) with milder hypertrophy (mean wall thickness ≈14 mm), lower prevalence of obstruction (15%), but a higher incidence of apical aneurysm (22%) compared to sarcomeric HCM ([PMID:39606411]). Biallelic ALPK3 cases manifest early-onset HCM with webbed neck and Noonan-like features, illustrating allelic and dosage effects ([PMID:37973666]).

Functional studies demonstrate that ALPK3 is a cardiac pseudokinase localized to the sarcomere M-band. Loss-of-function results in mislocalization of myomesin proteins and dysregulation of M-band turnover, leading to sarcomere disarray and impaired force buffering ([PMID:36321451]). Patient-derived iPSC and ESC cardiomyocytes lacking ALPK3 show disordered sarcomeres and abnormal calcium handling ([PMID:27106955]), while global knockout mice develop cardiac dilation transitioning to hypertrophy, mirroring human disease ([PMID:40135575]).

Although rare oligogenic cases indicate incomplete cosegregation, the preponderance of evidence from multiple cohorts, family studies, and functional assays supports a definitive role for heterozygous ALPK3 truncating variants in autosomal dominant HCM. Routine inclusion of ALPK3 in clinical genetic testing panels will enhance diagnostic yield and guide management.

References

• Cold Spring Harbor molecular case studies • 2017 • ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features. PMID:28630369
• European heart journal • 2021 • Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy. PMID:34263907
• medRxiv : the preprint server for health sciences • 2024 • ALPK3 heterozygous truncating variants cause late-onset hypertrophic cardiomyopathy with frequent apical involvement and apical aneurysm. PMID:39606411
• European heart journal • 2016 • ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy. PMID:27106955
• Circulation • 2022 • Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere. PMID:36321451
• Journal of cardiovascular translational research • 2023 • Compound Heterozygosity for Late-Onset Cardiomyopathy-Causative ALPK3 Coding Variant and Novel Intronic Variant Cause Infantile Hypertrophic Cardiomyopathy. PMID:37973666
• Circulation research • 2017 • A Potential Oligogenic Etiology of Hypertrophic Cardiomyopathy: A Classic Single-Gene Disorder. PMID:28223422
• Nature reviews. Cardiology • 2022 • Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies. PMID:34526680
• Journal of the American Heart Association • 2025 • α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function. PMID:40135575

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