Nature Communications

Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia

B Benita Menden R Rana D. Incebacak Eltemur G German Demidov M Marc Sturm J Joohyun Park C Chrisovalantou Huridou F Florian Fath A Astrid Nümann A Alexander Baumann I Illja J. Diets C Claudia Dufke M Martin Regensburger M Maria Rönnefarth V Vera Wilke S Stefan Vielhaber T Tim W. Rattay Z Zacharias Kohl S Susana Peralta P Priscila Pereira Sena M Melanie Kellner N Nadine Weissert A Andreas Traschütz L Lena Zeltner K Kai Boelmans N Natalie Deininger L Leon Schütz C Caspar Gross A Ana Beatriz Hinojosa Amaya K Katrin Raupach H Holger Hengel F Florian Harmuth J Jakob Admard I Ingrid Bader S Sarah Baumann F Friedemann Bender A Andrea Bevot A Almut Bischoff F Felix Boschann R Rebecca Buchert D Daniel Buchzik N Nicolas Casadei (Institute of Medical Genetics and Applied Genomics, University of Tuebingen) C Claudia B. Catarino I Isabell Cordts K Kirsten Cremer M Marion Doebler-Neumann N Nadja Ehmke M Miriam Elbracht R Ruth J. Falb T Thomas Feindt Z Zofia Fleszar L Lea Gerstner D Dieter Gläser U Ute Grasshoff S Sarah Grosch K Kathrin Grundmann A Alexander Gutschalk M Manja Haaga S Stefanie Hayer U Ute Hehr Y Yorck Hellenbroich W Wolfram Henn B Barbara Herr R Rebecca Herzog V Veronka Horber J Jonas Deppe N Nadja Kaiser C Christiane Kehrer M Martin Kehrer J Jan Kern C Christoph Keßler K Katharina Khuller H Hannah Klinkhammer (Institute for Medical Biometry and Statistics) U Urania Kotzaeridou P Peter Krawitz M Martina Kreiss H Hanna Küpper A Alice Kuster L Lucia Laugwitz A Anne Lesemann N Nadine Lichey T Tobias Linden B Boris Macek J Janine Magg E Elisabeth Mangold E Eva Manka I Iris Marquardt K Karl Mehnert D David Mengel S Susanne Morlot B Barbara Oehl-Jaschkowitz M Martje G. Pauly M Melanie Philipp F Florentine Radelfahr M Maren Rautenberg A Angelika Riess C Carsten Saft B Beate Schlotter-Weigel A Axel Schmidt E Eva M. C. Schwaibold V Veronika Spahlinger S Stephanie Spranger K Katharina Marie Steiner C Claudia Stendel A Andreas Thieme A Andreas Tzschach A Ana Velic S Sarah Wiethoff C Carlo Wilke S Stephan Züchner S Simone Zittel N Nienke van Os R Ralf A. Husain M Marcus Deschauer F Felix Distelmaier A Andreas Dufke H Holm Graessner B Bernhard Hemmer H Heike Jacobi T Thomas Klockgether T Thomas Klopstock X Xenia Kobeleva G Georg-Christoph Korenke A Alma Kuechler G Gregor Kuhlenbäumer I Ingo Kurth H Huu Phuc Nguyen (Department of Human Genetics, Ruhr University Bochum) G Gilbert Wunderlich K Kirsten E. Zeuner S Stephan Klebe M Michaela Auer-Grumbach M Michaela Butryn J Jürgen Winkler (Department of Molecular Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg) D Dagmar Timmann M Matthis Synofzik B Bart van de Warrenburg R Rebecca Schüle L Ludger Schöls S Stephan Ossowski O Olaf Riess (Institute of Medical Genetics and Applied Genomics, University of Tuebingen) J Jonasz J. Weber T Tobias B. Haack

Abstract

Abstract Most patients with a rare movement disorder (MD) do not receive a molecular diagnosis, and the underlying genetic variants and mediating genes remain elusive. Here, we evaluate the diagnostic accuracy of conventional and next-generation sequencing-based genetic testing strategies in a cohort of 2,811 individuals with ataxia, spastic paraplegia and dystonia. Exome sequencing establishes genetic diagnoses in 19.3% of cases, and specificity of phenotypic features and age at testing are positive predictors. Genome analysis ‘beyond the exome’ increases the diagnostic yield by 7.5%, mostly due to the improved detection of structural variants and repeat expansions. Unsolved cases are included in the Solve-RD cohort and subjected to gene-burden analysis, providing evidence for loss-of-function variants in X-chromosomal CD99L2 causing spastic ataxia. Cellular studies show that the transmembrane protein CD99L2 occurs mainly in a ubiquitinated form and serves as an activating interactor of the calcium-dependent protease CAPN1. Ablation of cytoplasmic or extracellular domains of CD99L2 leads to its intracellular mislocalization and abrogation of its interplay with CAPN1. Transcriptome analysis in CD99L2 patient-derived fibroblasts reveals synaptic function-specific disturbances. Impaired CAPN1 activation and dysregulation of downstream neuronal pathways constitute the likely molecular cause for neurodegeneration.

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Article Details

Volume / Issue Vol. 17, Issue 1
Published February 14, 2026
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio
ISSN: 2041-1723 Open Access Life Sciences

Authors (141)

B

Benita Menden

R

Rana D. Incebacak Eltemur

G

German Demidov

M

Marc Sturm

J

Joohyun Park

C

Chrisovalantou Huridou

F

Florian Fath

A

Astrid Nümann

A

Alexander Baumann

I

Illja J. Diets

C

Claudia Dufke

M

Martin Regensburger

M

Maria Rönnefarth

V

Vera Wilke

S

Stefan Vielhaber

T

Tim W. Rattay

Z

Zacharias Kohl

S

Susana Peralta

P

Priscila Pereira Sena

M

Melanie Kellner

N

Nadine Weissert

A

Andreas Traschütz

L

Lena Zeltner

K

Kai Boelmans

N

Natalie Deininger

L

Leon Schütz

C

Caspar Gross

A

Ana Beatriz Hinojosa Amaya

K

Katrin Raupach

H

Holger Hengel

F

Florian Harmuth

J

Jakob Admard

I

Ingrid Bader

S

Sarah Baumann

F

Friedemann Bender

A

Andrea Bevot

A

Almut Bischoff

F

Felix Boschann

R

Rebecca Buchert

D

Daniel Buchzik

N

Nicolas Casadei

Institute of Medical Genetics and Applied Genomics, University of Tuebingen

C

Claudia B. Catarino

I

Isabell Cordts

K

Kirsten Cremer

M

Marion Doebler-Neumann

N

Nadja Ehmke

M

Miriam Elbracht

R

Ruth J. Falb

T

Thomas Feindt

Z

Zofia Fleszar

L

Lea Gerstner

D

Dieter Gläser

U

Ute Grasshoff

S

Sarah Grosch

K

Kathrin Grundmann

A

Alexander Gutschalk

M

Manja Haaga

S

Stefanie Hayer

U

Ute Hehr

Y

Yorck Hellenbroich

W

Wolfram Henn

B

Barbara Herr

R

Rebecca Herzog

V

Veronka Horber

J

Jonas Deppe

N

Nadja Kaiser

C

Christiane Kehrer

M

Martin Kehrer

J

Jan Kern

C

Christoph Keßler

K

Katharina Khuller

H

Hannah Klinkhammer

Institute for Medical Biometry and Statistics

U

Urania Kotzaeridou

P

Peter Krawitz

M

Martina Kreiss

H

Hanna Küpper

A

Alice Kuster

L

Lucia Laugwitz

A

Anne Lesemann

N

Nadine Lichey

T

Tobias Linden

B

Boris Macek

J

Janine Magg

E

Elisabeth Mangold

E

Eva Manka

I

Iris Marquardt

K

Karl Mehnert

D

David Mengel

S

Susanne Morlot

B

Barbara Oehl-Jaschkowitz

M

Martje G. Pauly

M

Melanie Philipp

F

Florentine Radelfahr

M

Maren Rautenberg

A

Angelika Riess

C

Carsten Saft

B

Beate Schlotter-Weigel

A

Axel Schmidt

E

Eva M. C. Schwaibold

V

Veronika Spahlinger

S

Stephanie Spranger

K

Katharina Marie Steiner

C

Claudia Stendel

A

Andreas Thieme

A

Andreas Tzschach

A

Ana Velic

S

Sarah Wiethoff

C

Carlo Wilke

S

Stephan Züchner

S

Simone Zittel

N

Nienke van Os

R

Ralf A. Husain

M

Marcus Deschauer

F

Felix Distelmaier

A

Andreas Dufke

H

Holm Graessner

B

Bernhard Hemmer

H

Heike Jacobi

T

Thomas Klockgether

T

Thomas Klopstock

X

Xenia Kobeleva

G

Georg-Christoph Korenke

A

Alma Kuechler

G

Gregor Kuhlenbäumer

I

Ingo Kurth

H

Huu Phuc Nguyen

Department of Human Genetics, Ruhr University Bochum

G

Gilbert Wunderlich

K

Kirsten E. Zeuner

S

Stephan Klebe

M

Michaela Auer-Grumbach

M

Michaela Butryn

J

Jürgen Winkler

Department of Molecular Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

D

Dagmar Timmann

M

Matthis Synofzik

B

Bart van de Warrenburg

R

Rebecca Schüle

L

Ludger Schöls

S

Stephan Ossowski

O

Olaf Riess

Institute of Medical Genetics and Applied Genomics, University of Tuebingen

J

Jonasz J. Weber

T

Tobias B. Haack

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