Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A)

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). / Kaur, Simranpreet; Van Bergen, Nicole J.; Verhey, Kristen J.; Nowell, Cameron J.; Budaitis, Breane; Yue, Yang; Ellaway, Carolyn; Brunetti-Pierri, Nicola; Cappuccio, Gerarda; Bruno, Irene; Boyle, Lia; Nigro, Vincenzo; Torella, Annalaura; Roscioli, Tony; Cowley, Mark J.; Massey, Sean; Sonawane, Rhea; Burton, Matthew D.; Schonewolf-Greulich, Bitten; Tümer, Zeynep; Chung, Wendy K.; Gold, Wendy A.; Christodoulou, John.

I: Human Mutation, Bind 41, Nr. 10, 2020, s. 1761-1774.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Kaur, S, Van Bergen, NJ, Verhey, KJ, Nowell, CJ, Budaitis, B, Yue, Y, Ellaway, C, Brunetti-Pierri, N, Cappuccio, G, Bruno, I, Boyle, L, Nigro, V, Torella, A, Roscioli, T, Cowley, MJ, Massey, S, Sonawane, R, Burton, MD, Schonewolf-Greulich, B, Tümer, Z, Chung, WK, Gold, WA & Christodoulou, J 2020, 'Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A)', Human Mutation, bind 41, nr. 10, s. 1761-1774. https://doi.org/10.1002/humu.24079

APA

Kaur, S., Van Bergen, N. J., Verhey, K. J., Nowell, C. J., Budaitis, B., Yue, Y., Ellaway, C., Brunetti-Pierri, N., Cappuccio, G., Bruno, I., Boyle, L., Nigro, V., Torella, A., Roscioli, T., Cowley, M. J., Massey, S., Sonawane, R., Burton, M. D., Schonewolf-Greulich, B., ... Christodoulou, J. (2020). Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). Human Mutation, 41(10), 1761-1774. https://doi.org/10.1002/humu.24079

Vancouver

Kaur S, Van Bergen NJ, Verhey KJ, Nowell CJ, Budaitis B, Yue Y o.a. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). Human Mutation. 2020;41(10):1761-1774. https://doi.org/10.1002/humu.24079

Author

Kaur, Simranpreet ; Van Bergen, Nicole J. ; Verhey, Kristen J. ; Nowell, Cameron J. ; Budaitis, Breane ; Yue, Yang ; Ellaway, Carolyn ; Brunetti-Pierri, Nicola ; Cappuccio, Gerarda ; Bruno, Irene ; Boyle, Lia ; Nigro, Vincenzo ; Torella, Annalaura ; Roscioli, Tony ; Cowley, Mark J. ; Massey, Sean ; Sonawane, Rhea ; Burton, Matthew D. ; Schonewolf-Greulich, Bitten ; Tümer, Zeynep ; Chung, Wendy K. ; Gold, Wendy A. ; Christodoulou, John. / Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). I: Human Mutation. 2020 ; Bind 41, Nr. 10. s. 1761-1774.

Bibtex

@article{1528048a0432400ab34433ec28e93e95,
title = "Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A)",
abstract = "Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here, we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.",
keywords = "KAND, KIF1A, kinesin, MECP2, microtubule, neurite tip accumulation, Rett syndrome",
author = "Simranpreet Kaur and {Van Bergen}, {Nicole J.} and Verhey, {Kristen J.} and Nowell, {Cameron J.} and Breane Budaitis and Yang Yue and Carolyn Ellaway and Nicola Brunetti-Pierri and Gerarda Cappuccio and Irene Bruno and Lia Boyle and Vincenzo Nigro and Annalaura Torella and Tony Roscioli and Cowley, {Mark J.} and Sean Massey and Rhea Sonawane and Burton, {Matthew D.} and Bitten Schonewolf-Greulich and Zeynep T{\"u}mer and Chung, {Wendy K.} and Gold, {Wendy A.} and John Christodoulou",
year = "2020",
doi = "10.1002/humu.24079",
language = "English",
volume = "41",
pages = "1761--1774",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "JohnWiley & Sons, Inc.",
number = "10",

}

RIS

TY - JOUR

T1 - Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A)

AU - Kaur, Simranpreet

AU - Van Bergen, Nicole J.

AU - Verhey, Kristen J.

AU - Nowell, Cameron J.

AU - Budaitis, Breane

AU - Yue, Yang

AU - Ellaway, Carolyn

AU - Brunetti-Pierri, Nicola

AU - Cappuccio, Gerarda

AU - Bruno, Irene

AU - Boyle, Lia

AU - Nigro, Vincenzo

AU - Torella, Annalaura

AU - Roscioli, Tony

AU - Cowley, Mark J.

AU - Massey, Sean

AU - Sonawane, Rhea

AU - Burton, Matthew D.

AU - Schonewolf-Greulich, Bitten

AU - Tümer, Zeynep

AU - Chung, Wendy K.

AU - Gold, Wendy A.

AU - Christodoulou, John

PY - 2020

Y1 - 2020

N2 - Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here, we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.

AB - Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here, we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.

KW - KAND

KW - KIF1A

KW - kinesin

KW - MECP2

KW - microtubule

KW - neurite tip accumulation

KW - Rett syndrome

U2 - 10.1002/humu.24079

DO - 10.1002/humu.24079

M3 - Journal article

C2 - 32652677

AN - SCOPUS:85088360250

VL - 41

SP - 1761

EP - 1774

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 10

ER -

ID: 253401879