MAPKBP1 – Nephronophthisis

Biallelic mutations in MAPKBP1 have been implicated in a late‑onset form of nephronophthisis. Recent studies identified patients with homozygous splice‑site variants in MAPKBP1, uncovered using exome sequencing and homozygosity mapping (PMID:32505465). These variants are associated with chronic kidney disease that lacks classical ciliopathy features and instead presents with milder clinical manifestations.

The genetic evidence is compelling for an autosomal recessive mode of inheritance. Affected individuals from independent cohorts have demonstrated segregation of the biallelic splice‑site variants within consanguineous or familial settings (PMID:32505465). Although a specific HGVS‐formatted variant has not been explicitly provided, the identification of such causative variants supports the pathogenic role of MAPKBP1 in nephronophthisis.

Functional studies further substantiate these findings by demonstrating that the identified splice‑site changes result in truncation of the C‑terminal coiled‑coil domain. This truncation disrupts MAPKBP1 dimerization and impairs its centriolar recruitment, weakening its normal microtubule‐binding function during cell division (PMID:32505465).

Additional experiments using co‑immunoprecipitation and localization assays confirmed that the disruption of dimerization abrogates the proper intracellular targeting of MAPKBP1. Such experimental concordance reinforces that loss‑of‑function is the likely mechanism underlying the nephronophthisis phenotype.

Integrating both the genetic and experimental data yields a coherent narrative: disruption of MAPKBP1 activity via biallelic splice‑site variants leads to impaired centrosomal and microtubule associations that are critical for normal renal signaling. This strong gene‑disease association has important diagnostic and prognostic relevance for patients with unexplained chronic kidney disease, particularly in adult populations with features of nephronophthisis.

Key take‑home sentence: The combined genetic and functional evidence supports a strong clinical association between MAPKBP1 loss‑of‑function and nephronophthisis, advocating for its inclusion in diagnostic panels for chronic kidney disease.

References

• Kidney international • 2020 • Novel nephronophthisis‑associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment PMID:32505465
• Kidney international • 2016 • Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood‑onset increased renal echogenicity PMID:26489029

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