Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis Jérôme Maluenda, Constance.

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Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis Jérôme Maluenda, Constance Manso, Loic Quevarec, Alexandre Vivanti, Florent Marguet, Marie Gonzales, Fabien Guimiot, Florence Petit, Annick Toutain, Sandra Whalen, Romulus Grigorescu, Anne Dieux Coeslier, Marta Gut, Ivo Gut, Annie Laquerrière, Jérôme Devaux, Judith Melki The American Journal of Human Genetics Volume 99, Issue 4, Pages 928-933 (October 2016) DOI: 10.1016/j.ajhg.2016.07.021 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Mutations Identified in GLDN in AMC-Affected Families (A) Pedigrees for families 1, 2, 3, and 4 are shown. Arrows indicate mutant nucleotide positions. The affected individuals carry either compound heterozygous (families 1 and 3) or homozygous (families 2 and 4) mutations. The nucleotide and amino acid changes are indicated with respect to the GenBank: NM_181789.2 and Genbank: NP_861454.2 reference sequences, respectively. Open symbols, unaffected; filled symbols, affected. (B) Sequencing of RT-PCR product from the RNA of the family 3 affected individual, II:1, (P) and a control individual (C) is shown. RT-PCR analysis was performed from RNA after reverse transcription with random hexamers. Long-range PCR amplification was carried out with Advantage GC Genomic LA polymerase (Clontech), then Sanger sequencing was performed from the RT-PCR products with primers GLDN-Ex1Fq and GLDN-Ex10Rq (Table S1). Sequence analysis revealed the nonsense mutation, only indicating that the allelic splice donor mutation leads to either a retention of large intronic sequence or instability of the corresponding transcript. (C) Location of mutations relative to the predicted protein domains of gliomedin is shown. The American Journal of Human Genetics 2016 99, 928-933DOI: (10.1016/j.ajhg.2016.07.021) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Transmission Electron Microscopy Analysis of Nerve in the Family 1 Affected Individual II:1 Carrying Deleterious GLDN Mutations Tissue samples were fixed in a 2% glutaraldehyde fixative solution, post-fixed with osmium tetroxide, and embedded in resin epoxy. Semi-thin sections were stained with toluidine blue. Ultra-thin sections were contrasted with uranyl acetate and lead citrate and examined under a PHILIPS CM10 transmission electron microscope. Longitudinal sciatic nerve sections of the affected fetus, displaying increased length of the node of Ranvier (A and B), are shown, as is that of an age-matched (33 w.g.) control indiviudal (C). Scale bars represent 3 μm. The American Journal of Human Genetics 2016 99, 928-933DOI: (10.1016/j.ajhg.2016.07.021) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 Mutations in GLDN Affect the Surface Localization of the Protein Human gliomedin cDNA was amplified by PCR from a human placental cDNA library and sub-cloned into pcDNA3.1 (Thermofisher) at KpnI and XbaI sites, and a myc-tag epitope was inserted at the extracellular C terminus. Mutations found in the affected individuals (c.1423G>C, c.758delC, and c.95C>A) were inserted into cDNA with PrimeSTAR HS DNA polymerase (Clontech). All constructs were sequenced through the entire coding region. CHO cells transfected with myc-tagged human gliomedin (hGLDN) were incubated with mouse antibodies against myc before fixation to label surface myc (red) and after fixation and permeabilization to label total myc (green). Nuclei are stained with DAPI (blue). WT gliomedin (A) is readily localized at the cell surface. By contrast, p.Ala32Glu (B), p.Ala475Pro (C), and p.Pro253Leufs∗51 (D) variants strongly impacted the surface localization of gliomedin. Scale bars represent 10 μm. The American Journal of Human Genetics 2016 99, 928-933DOI: (10.1016/j.ajhg.2016.07.021) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 4 NF186 Binding is Disrupted by GLDN Mutations CHO cells transfected with myc-tagged human gliomedin (hGLDN, green) were incubated with the extracellular domain of NF186 fused to human IgG Fc (NF186-Fc, red). NF186-Fc was expressed in human embryonic kidney cells and purified with Protein A-Sepharose beads (Sigma-Aldrich). Nuclei are stained with DAPI (blue). NF186-Fc bound to cells transfected with WT gliomedin (A), but did not bind to p.Ala32Glu (B), p.Ala475Pro (C), or p.Pro253Leufs∗51 (D) mutants. Scale bars represent 10 μm. The American Journal of Human Genetics 2016 99, 928-933DOI: (10.1016/j.ajhg.2016.07.021) Copyright © 2016 American Society of Human Genetics Terms and Conditions