NEK3 and Situs Inversus

The association between NEK3 (HGNC:7746) and situs inversus (MONDO_0010029) is supported by multiple lines of evidence. Two unrelated family trios (PMID:33230144) were identified with compound heterozygous mutations in NEK3, providing a robust genetic basis for the observed laterality defects. Detailed case reports highlight that the affected individuals presented with abnormal cardiac left–right patterning, a hallmark feature of situs inversus.

Genetic evidence comprises identification of loss-of-function events, including splice-site and frameshift variants. In these families, variants such as c.356A>G (p.His119Arg) were observed, underscoring a deleterious impact on NEK3 function (PMID:33230144). The variant spectrum, which also includes other LoF alterations, is consistent with an autosomal recessive mode of inheritance.

Functional studies further confirmed the pathogenicity of NEK3 mutations. In vitro knockdown experiments in human retinal pigment epithelial cells revealed that NEK3 depletion leads to marked α-tubulin deacetylation as well as downregulation of inner ring nucleoporins, particularly NUP205, NUP188, and NUP155. Transmission electron microscopy (TEM) provided ultrastructural evidence of defective cilia, firmly linking the molecular defect to the laterality disorder.

Mechanistic insights indicate that biallelic loss-of-function NEK3 mutations result in absence of functional NEK3 protein. This loss affects downstream targets such as SIRT2, thereby promoting deacetylation of α-tubulin and impairing cilia structure. The decreased levels of critical nucleoporins further compromise the nuclear pore complex, contributing to abnormal left–right patterning observed in patients.

Integration of the genetic and experimental results reveals a coherent narrative: the compound heterozygous mutations in NEK3 disrupt ciliary function via a well-defined molecular cascade affecting tubulin acetylation and nuclear pore integrity. The convergence of clinical, genetic, and functional data substantiates a strong association between NEK3 and situs inversus.

Additional supportive evidence, including segregation analysis within the reported families and concordant functional assays, bolsters diagnostic decision‑making and commercial application. This association provides a clear framework for genetic testing and targeted therapeutics in individuals with laterality defects.

Key Take‑home Sentence: NEK3 loss‑of‑function mutations represent a strong and actionable diagnostic marker for situs inversus, integrating robust genetic and functional evidence.

References

• Cell death & disease • 2020 • Biallelic loss of function NEK3 mutations deacetylate α‑tubulin and downregulate NUP205 that predispose individuals to cilia‑related abnormal cardiac left‑right patterning PMID:33230144

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