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Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia

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Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia. / Schob, Claudia; Hempel, Maja; Brozkova, Dana Safka; Jiang, Huafang; Kim, Soo Yeon; Batzir, Nurit Assia; Orenstein, Naama; Bierhals, Tatjana; Johannsen, Jessika; Meszarosova, Anna Uhrova; Chae, Jong-Hee; Seeman, Pavel; Woidy, Mathias; Fang, Fang; Kubisch, Christian; Kindler, Stefan; Denecke, Jonas.

In: ANN NEUROL, Vol. 90, No. 5, 11.2021, p. 738-750.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Schob, C, Hempel, M, Brozkova, DS, Jiang, H, Kim, SY, Batzir, NA, Orenstein, N, Bierhals, T, Johannsen, J, Meszarosova, AU, Chae, J-H, Seeman, P, Woidy, M, Fang, F, Kubisch, C, Kindler, S & Denecke, J 2021, 'Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia', ANN NEUROL, vol. 90, no. 5, pp. 738-750. https://doi.org/10.1002/ana.26228

APA

Schob, C., Hempel, M., Brozkova, D. S., Jiang, H., Kim, S. Y., Batzir, N. A., Orenstein, N., Bierhals, T., Johannsen, J., Meszarosova, A. U., Chae, J-H., Seeman, P., Woidy, M., Fang, F., Kubisch, C., Kindler, S., & Denecke, J. (2021). Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia. ANN NEUROL, 90(5), 738-750. https://doi.org/10.1002/ana.26228

Vancouver

Schob C, Hempel M, Brozkova DS, Jiang H, Kim SY, Batzir NA et al. Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia. ANN NEUROL. 2021 Nov;90(5):738-750. https://doi.org/10.1002/ana.26228

Bibtex

@article{48366435933c496d917eff04f9b24aed,
title = "Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia",
abstract = "OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation.METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays.RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction.INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.",
author = "Claudia Schob and Maja Hempel and Brozkova, {Dana Safka} and Huafang Jiang and Kim, {Soo Yeon} and Batzir, {Nurit Assia} and Naama Orenstein and Tatjana Bierhals and Jessika Johannsen and Meszarosova, {Anna Uhrova} and Jong-Hee Chae and Pavel Seeman and Mathias Woidy and Fang Fang and Christian Kubisch and Stefan Kindler and Jonas Denecke",
note = "This article is protected by copyright. All rights reserved.",
year = "2021",
month = nov,
doi = "10.1002/ana.26228",
language = "English",
volume = "90",
pages = "738--750",
journal = "ANN NEUROL",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "5",

}

RIS

TY - JOUR

T1 - Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia

AU - Schob, Claudia

AU - Hempel, Maja

AU - Brozkova, Dana Safka

AU - Jiang, Huafang

AU - Kim, Soo Yeon

AU - Batzir, Nurit Assia

AU - Orenstein, Naama

AU - Bierhals, Tatjana

AU - Johannsen, Jessika

AU - Meszarosova, Anna Uhrova

AU - Chae, Jong-Hee

AU - Seeman, Pavel

AU - Woidy, Mathias

AU - Fang, Fang

AU - Kubisch, Christian

AU - Kindler, Stefan

AU - Denecke, Jonas

N1 - This article is protected by copyright. All rights reserved.

PY - 2021/11

Y1 - 2021/11

N2 - OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation.METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays.RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction.INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.

AB - OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation.METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays.RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction.INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.

U2 - 10.1002/ana.26228

DO - 10.1002/ana.26228

M3 - SCORING: Journal article

C2 - 34564892

VL - 90

SP - 738

EP - 750

JO - ANN NEUROL

JF - ANN NEUROL

SN - 0364-5134

IS - 5

ER -