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Neurology Genetics
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February 2018; 4 (1) ArticleOpen Access

Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function

Natalia Mendoza-Ferreira, Marie Coutelier, Eva Janzen, Seyyedmohsen Hosseinibarkooie, Heiko Löhr, Svenja Schneider, Janine Milbradt, Mert Karakaya, Markus Riessland, Christian Pichlo, Laura Torres-Benito, Andrew Singleton, Stephan Zuchner, Alexis Brice, Alexandra Durr, Matthias Hammerschmidt, Giovanni Stevanin, Brunhilde Wirth
First published January 19, 2018, DOI: https://doi.org/10.1212/NXG.0000000000000209
Natalia Mendoza-Ferreira
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Marie Coutelier
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Eva Janzen
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Seyyedmohsen Hosseinibarkooie
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Heiko Löhr
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Svenja Schneider
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Janine Milbradt
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Mert Karakaya
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Markus Riessland
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Christian Pichlo
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Laura Torres-Benito
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Andrew Singleton
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Stephan Zuchner
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Alexis Brice
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Alexandra Durr
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Matthias Hammerschmidt
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Giovanni Stevanin
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Brunhilde Wirth
From Institute of Human Genetics (N.M.-F., E.J., S.H., S.S., J.M., M.K., M.R., L.T.-B., B.W.), Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany; Institute for Zoology, Developmental Biology (H.L., M.H.), Institute of Biochemistry (C.P.), University of Cologne, Germany; Institut du Cerveau et de la Moelle épinière (M.C., A.B., A.D., G.S.), INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, France; Ecole Pratique des Hautes Etudes (M.C., G.S.), PSL Research University, Paris, France; Laboratory of Molecular and Cellular Neuroscience (M.R.), The Rockefeller University, New York, NY; Laboratory of Neurogenetics (A.S.), National Institute on Aging, National Institutes of Health, Bethesda, MD; John P. Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, FL; and APHP (A.B., A.D., G.S.), Hôpital de la Pitié-Salpêtrière, Centre de réference de neurogénétique, Paris, France.
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Full PDF
Citation
Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function
Natalia Mendoza-Ferreira, Marie Coutelier, Eva Janzen, Seyyedmohsen Hosseinibarkooie, Heiko Löhr, Svenja Schneider, Janine Milbradt, Mert Karakaya, Markus Riessland, Christian Pichlo, Laura Torres-Benito, Andrew Singleton, Stephan Zuchner, Alexis Brice, Alexandra Durr, Matthias Hammerschmidt, Giovanni Stevanin, Brunhilde Wirth
Neurol Genet Feb 2018, 4 (1) e209; DOI: 10.1212/NXG.0000000000000209

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Abstract

Objective: To ascertain the genetic and functional basis of complex autosomal recessive cerebellar ataxia (ARCA) presented by 2 siblings of a consanguineous family characterized by motor neuropathy, cerebellar atrophy, spastic paraparesis, intellectual disability, and slow ocular saccades.

Methods: Combined whole-genome linkage analysis, whole-exome sequencing, and focused screening for identification of potential causative genes were performed. Assessment of the functional consequences of the mutation on protein function via subcellular fractionation, size-exclusion chromatography, and fluorescence microscopy were done. A zebrafish model, using Morpholinos, was generated to study the pathogenic effect of the mutation in vivo.

Results: We identified a biallelic 3-bp deletion (p.K19del) in CHP1 that cosegregates with the disease. Neither focused screening for CHP1 variants in 2 cohorts (ARCA: N = 319 and NeurOmics: N = 657) nor interrogating GeneMatcher yielded additional variants, thus revealing the scarcity of CHP1 mutations. We show that mutant CHP1 fails to integrate into functional protein complexes and is prone to aggregation, thereby leading to diminished levels of soluble CHP1 and reduced membrane targeting of NHE1, a major Na+/H+ exchanger implicated in syndromic ataxia-deafness. Chp1 deficiency in zebrafish, resembling the affected individuals, led to movement defects, cerebellar hypoplasia, and motor axon abnormalities, which were ameliorated by coinjection with wild-type, but not mutant, human CHP1 messenger RNA.

Conclusions: Collectively, our results identified CHP1 as a novel ataxia-causative gene in humans, further expanding the spectrum of ARCA-associated loci, and corroborated the crucial role of NHE1 within the pathogenesis of these disorders.

GLOSSARY

ARCA=
autosomal recessive cerebellar ataxia;
CaP-MN=
caudal primary motor neuron;
cDNA=
complementary DNA;
EGFR=
epidermal growth factor receptor;
GFP=
green fluorescent protein;
HMW=
high molecular weight;
HPRT=
hypoxanthine-guanine phosphoribosyltransferase;
HSP90=
heat shock protein 90;
KO=
knockout;
LKS=
Lichtenstein-Knorr syndrome;
LOD=
Logarithm of the odds;
mRNA=
messenger RNA;
MO=
Morpholino;
OE=
overexpression;
RT-PCR=
reverse transcription PCR;
SEC=
size-exclusion chromatography;
WB=
Western blot;
WES=
whole-exome sequencing;
WT=
wild type

Footnotes

  • Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was funded by the authors.

  • Received August 11, 2017.
  • Accepted in final form August 22, 2017.
  • Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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