MPLKIP – Trichothiodystrophy

MPLKIP has been strongly implicated in the etiology of trichothiodystrophy, a multisystem disorder characterized by brittle hair, intellectual impairment, and hypogonadism. The association is supported by evidence from multiple case reports and multi‐patient studies that collectively demonstrate an autosomal recessive inheritance pattern with robust segregation data and concordant functional assessment (PMID:26518168, PMID:16977596).

Genetic evidence establishes that loss‑of‑function variants in MPLKIP are causative for trichothiodystrophy. Several independent families have been reported with frameshift and deletion mutations, including the recurrent variant c.122dup (p.Arg42fs) (PMID:16977596, PMID:25290684). Segregation analyses in consanguineous and multiplex kindreds further support an autosomal recessive mechanism.

Functional studies have tested the impact of MPLKIP mutations on RNA processing and protein stability. For instance, splicing assays and protein–interaction studies reveal that aberrant splicing events and consequent protein truncation disrupt DBR1 stabilization, which is critical for proper lariat debranching and ectodermal differentiation (PMID:37800682, PMID:26880286). These findings elucidate a clear pathogenic mechanism underlying trichothiodystrophy.

While some reports note phenotypic variability—particularly with differences in photosensitivity—the overall consistency of variant segregation, clinical findings, and experimental concordance reinforces the gene–disease relationship. In several studies, even in the absence of photosensitivity, affected individuals display hallmark features such as brittle hair, intellectual disability, and hypogonadism, thereby underscoring allelic heterogeneity within the MPLKIP spectrum (PMID:30580289, PMID:19681155).

Data integration from both genetic and functional assessments supports a strong association between MPLKIP mutations and trichothiodystrophy. The recurrent nature of loss‑of‑function variants, evidenced through multiple unrelated probands and segregation across different families, attests to the clinical relevance of this gene in diagnostic screening.

Key Take‑home: The strong genetic and functional evidence validating the MPLKIP–trichothiodystrophy association renders this marker highly valuable for clinical diagnosis, risk assessment, and guiding future research into pathomechanisms and therapy development.

References

• European Journal of Medical Genetics • 2015 • A novel mutation in the C7orf11 gene causes nonphotosensitive trichothiodystrophy in a multiplex highly consanguineous kindred PMID:26518168
• BMJ Case Reports • 2018 • PIBIDS syndrome in two Brazilian siblings PMID:30580289
• Human Mutation • 2007 • Mutations in the C7orf11 (TTDN1) gene in six nonphotosensitive trichothiodystrophy patients: no obvious genotype-phenotype relationships PMID:16977596
• American Journal of Medical Genetics. Part A • 2021 • A novel MPLKIP-variant in three Finnish patients with non-photosensitive trichothiodystrophy type 4 PMID:33729667
• The Journal of Investigative Dermatology • 2015 • Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype PMID:25290684
• American Journal of Medical Genetics. Part A • 2009 • New clinico-genetic classification of trichothiodystrophy PMID:19681155
• BMC Medical Genetics • 2016 • Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP PMID:26880286
• EMBO Molecular Medicine • 2023 • Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for proper lariat debranching and ectodermal differentiation PMID:37800682
• Molecular Cell • 2023 • A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy PMID:37369199
• DNA Repair • 2010 • Trichothiodystrophy: from basic mechanisms to clinical implications PMID:19931493

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