Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain Clare V. Logan,

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Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain Clare V. Logan, Judith Cossins, Pedro M. Rodríguez Cruz, David A. Parry, Susan Maxwell, Pilar Martínez-Martínez, Joey Riepsaame, Zakia A. Abdelhamed, Alice V.R. Lake, Maria Moran, Stephanie Robb, Gabriel Chow, Caroline Sewry, Philip M. Hopkins, Eamonn Sheridan, Sandeep Jayawant, Jacqueline Palace, Colin A. Johnson, David Beeson The American Journal of Human Genetics Volume 97, Issue 6, Pages 878-885 (December 2015) DOI: 10.1016/j.ajhg.2015.10.017 Copyright © 2015 The Authors Terms and Conditions

Figure 1 Features of Individuals with COL13A1 Mutations (A–D) Muscle biopsy from the quadriceps muscle of affected individual II:1 from family 1 at 6 months of age. (A) H&E staining shows abnormal variation in fiber size, few central nuclei, and occasional vacant peripheral vacuole-like areas. (B) Staining for NADH-tetrazolium reductase shows occasional fibers with a halo-like appearance. (C) ATPase staining at pH 4.6 shows several populations of fibers staining positive for fetal myosin. (D) Gömöri trichrome staining shows several hypercontracted fibers and enlarged mitochondria. Fiber size ranges from 4 to 18 μm. Scale bars represent 100 μm. (E) Repetitive nerve stimulation of left flexor hallucis brevis muscle (II:1 family 1) shows significant (>20%) decrement. The American Journal of Human Genetics 2015 97, 878-885DOI: (10.1016/j.ajhg.2015.10.017) Copyright © 2015 The Authors Terms and Conditions

Figure 2 Sequence Analysis of COL13A1 Mutations and Schematic Representations of COL13A1 and COL13A1 (A) Top: pedigree of affected individual II:1 in family 1. Bottom: IGV pileup of sequencing reads for individual II:1 (blue) and her unaffected mother, I:2 (pink). The red arrow indicates the homozygous frameshift mutation c.1171delG. The mother is heterozygous for this mutation. Numbers at the top represent physical locations (based on Ensembl genome assembly GRCh37), and nucleotides and amino acid residues are shown below. Individuals analyzed by WES are indicated by asterisks. (B) Top: pedigree of affected individuals II:1 and II:2 in family 2. Bottom: IGV pileup of sequencing reads for individual II:1 (pink). The red arrow indicates the homozygous splice-site mutation c.523−1delG. (C) Schematic of COL13A1, encoding transcript variant 1 (GenBank: NM_001130103.1), in chromosomal region 10q22. Vertical black bars represent coding exons, and red arrows indicate the locations of pathogenic mutations. Numbers represent physical locations (Ensembl genome assembly GRCh37). (D) Schematic of the full-length COL13A1 isoform 1 (GenBank: NP_001123575), including a short intracellular domain, a single transmembrane helix (TM; dark gray), and the extracellular region with three collagenous domains (COL1–COL3) separated by short non-collagenous domains (NC1–NC4). Each collagen domain has separate collagen helix repeats (pink boxes). The approximate location of the proprotease recognition site is indicated by the black arrow. Numbers indicate the amino acid residues composing each domain. The American Journal of Human Genetics 2015 97, 878-885DOI: (10.1016/j.ajhg.2015.10.017) Copyright © 2015 The Authors Terms and Conditions

Figure 3 COL13A1 Is Localized at the Human NMJ and Mediates Clustering of AChRs (A) In human muscle, COL13A1 (red) is enriched at endplate regions of NMJs marked by α-bungarotoxin (Butx; green). Scale bar represents 10 μm. (B) Immunofluorescence labeling of quadriceps muscle from individual 1 (affected individual II:1 in family 1), who carries the homozygous frameshift mutation COL13A1 c.1171delG, which causes loss of COL13A1 accumulation (red) at an NMJ marked by α-bungarotoxin (Butx; green). Scale bar represents 10 μm. (C) Normal expression and localization of markers for the NMJ (α-bungarotoxin [Butx]), the presynaptic terminal in NMJs (synaptophysin), terminal Schwann cells (S100β), the intersynaptic space (fasciculin), and postsynaptic proteins (DOK7 and MuSK) in individual 1. Scale bars represent 10 μm. (D) AChR-cluster analysis of the COL13A1 c.1171delG variant. Bar graphs show that the frameshift mutation caused the number of AChR clusters in differentiated mutant myotubes to be statistically significantly lower than that in mock transfected (wild-type) or non-transfected C2C12 myotubes (left panel), but there was no significant effect on average cluster length (right panel). Statistical analyses used one-way ANOVA with Tukey’s multiple-comparison test (∗∗∗p < 0.001). The American Journal of Human Genetics 2015 97, 878-885DOI: (10.1016/j.ajhg.2015.10.017) Copyright © 2015 The Authors Terms and Conditions