Novel compound heterozygous mutations in the <scp><i>PLEC</i></scp> gene in a neonate with epidermolysis bullosa simplex with pyloric atresia

Kaneyasu, Hidenobu; Takahashi, Kazumasa; Ohta, Naoki; Okada, Seigo; Kimura, Sasagu; Yasuno, Shuichiro; Murata, Susumu; Katsura, Shunsaku; Yamada, Naoyuki; Shiraishi, Koji; Tsuda, Junko; Miyai, Shunsuke; Kurahashi, Hiroki; Hasegawa, Shunji; Shimomura, Yutaka

doi:10.1111/1346-8138.16553

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Cited by 2 publications

References 14 publications

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Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion

Zrelski,

Hösele,

Kustermann

et al. 2024

Journal of Investigative Dermatology

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Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion

Zrelski,

Hösele,

Kustermann

et al. 2024

Journal of Investigative Dermatology

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Ciliopathy-associated missense mutations in IFT140 are hypomorphic and have edgetic effects on protein interaction networks

Leonhard

Diwan

Klose

et al. 2023

Preprint

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The mechanisms underlying recessive Mendelian diseases and the interplay between genotype and phenotype still need to be better understood. It is therefore necessary to characterise the functional effects of missense mutations at the protein level. Here we focus on missense mutations in the intraflagellar transport protein IFT140, which forms part of the IFT complex A (IFT-A), a crucial component of the ciliary machinery. Mutations in IFT140 can cause a vast spectrum of diseases belonging to the group of ciliopathies, reaching from isolated retinal dystrophy to severe skeletal abnormalities and multi-organ diseases such as Mainzer-Saldino and Jeune syndrome. We hypothesise that missense mutations in IFT140 are hypomorphic leading to quantitative effects on a subset of protein-protein interactions. This may affect complex stability as well as perturbations of protein interaction networks. In this work we assessed how 24 missense mutations in IFT140 affect interactions with other IFT and effector proteins using affinity purification coupled to mass spectrometry. Our data reveals that several mutations in IFT140 are hypomorphic and disrupt the stability of the IFT-A complex to varying degrees in a quantitative way. Allelic combination and the degree of IFT-A complex disruption in analysed missense mutations correlates with the severity of the observed phenotype in a subset of patients. In addition, we show that a distinct subset of mutations in IFT140 shows edgetic effects by disrupting specific PPIs rather than causing a total loss of IFT-A binding. This is the case e.g. with the disease-associated protein TULP3 which is involved in cilia-dependent sonic hedgehog signalling.

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Novel compound heterozygous mutations in the PLEC gene in a neonate with epidermolysis bullosa simplex with pyloric atresia

Cited by 2 publications

References 14 publications

Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion

Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion

Ciliopathy-associated missense mutations in IFT140 are hypomorphic and have edgetic effects on protein interaction networks

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