MAPKAPK5 – Neurocardiofaciodigital Syndrome

Mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5) encodes a serine/threonine kinase crucial for cytoskeletal dynamics and neurodevelopment. Biallelic pathogenic variants in MAPKAPK5 have been implicated in neurocardiofaciodigital syndrome (neurocardiofaciodigital syndrome), a rare autosomal recessive disorder characterized by global developmental delay, craniofacial dysmorphism, digital anomalies, and neuroradiological defects.

In a cohort of four patients from three consanguineous families, homozygous loss-of-function and missense MAPKAPK5 variants were identified presenting with severe global developmental delay, intellectual disability, cerebellar hypoplasia, hypomyelination, hypotonia, microcephaly, brachycephaly, digital anomalies, genitourinary defects, and failure to thrive ([PMID:36581449]). A separate study described three individuals from two unrelated families with homozygous truncating MAPKAPK5 variants and overlapping clinical features, including synpolydactyly and cardiac anomalies ([PMID:33442026]). Together, these reports encompass seven probands across five unrelated families and confirm autosomal recessive inheritance.

Variants include both premature truncating and missense alleles. A recurrent nonsense variant, c.1303C>T (p.Gln435Ter), was observed in one family and segregated with disease phenotype. No dominant-negative effects were reported, supporting a loss-of-function mechanism.

Patient-derived dermal fibroblasts harboring truncating MAPKAPK5 variants exhibited absent MAPKAPK5 protein expression, reduced ERK3 levels, and impaired F-actin recovery following latrunculin B treatment, consistent with disrupted cytoskeletal regulation. These findings corroborate the cellular impact of MAPKAPK5 deficiency and align with the human neurodevelopmental phenotype.

Contrastingly, MK5 knockout mice generated by homologous recombination display no overt developmental or behavioral abnormalities, suggesting species-specific or compensatory mechanisms in rodents ([PMID:14560018]). This discrepancy underscores the value of human cellular models in elucidating pathogenicity.

Collectively, genetic and functional data strongly support MAPKAPK5 loss of function as the cause of neurocardiofaciodigital syndrome. Clinical genetic testing of MAPKAPK5 should be considered in patients with unexplained global developmental delay, cerebellar hypoplasia, digital anomalies, and related features.

Key take-home: Biallelic MAPKAPK5 pathogenic variants cause a distinct autosomal recessive neurodevelopmental syndrome with consistent clinical and cellular signatures, guiding diagnostic and management strategies.

References

• Journal of medical genetics • 2023 • Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder. PMID:36581449
• Genetics in medicine • 2021 • Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly. PMID:33442026

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