Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus Pierre.

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Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus Pierre Cacciagli, Julie Sutera-Sardo, Ana Borges-Correia, Jean-Christophe Roux, Imen Dorboz, Jean-Pierre Desvignes, Catherine Badens, Marc Delepine, Mark Lathrop, Pierre Cau, Nicolas Lévy, Nadine Girard, Pierre Sarda, Odile Boespflug-Tanguy, Laurent Villard The American Journal of Human Genetics Volume 93, Issue 3, Pages 579-586 (September 2013) DOI: 10.1016/j.ajhg.2013.07.023 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and Identified Mutations (A) Pedigrees of the three families show the seven affected individuals and female carriers of a BCAP31 mutation. (B) Schematic representation of the human chromosome Xq28 region containing BCAP31 and flanking SLC6A8 and ABCD1. Exon numbers are provided, and arrows indicate the transcription orientation (cen, centromere; tel, telomere). UTRs are represented by open boxes, and the alternative 3′ UTR of SLC6A8 is hatched. The three mutations are indicated below the genes. The Xq28 deletion is numbered according to HGVS nomenclature: RefSeq NM_005629.3 for SLC6A8 and NM_001139441 for BCAP31. The American Journal of Human Genetics 2013 93, 579-586DOI: (10.1016/j.ajhg.2013.07.023) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Phenotype of the Affected Individuals (A) Facial dysmorphic features observed in the different affected members of the three families. Note the dystonic posture of the upper limbs of individuals F1-III.3 and F3-III.1. (B) Sagittal cerebral MRI sequence of person F1-III.2 at 11 months of age shows the atrophy of the cerebellar vermis (white arrow) (a). Axial cerebral MRI of individual F2-IV.1 at 6.5 years of age shows a mild abnormal hyperintense signal on the T2 sequence in the parieto-occipital white matter (b) and a normal hyperintense signal on the T1 sequence (c) (open white arrows), suggesting poor myelination. The American Journal of Human Genetics 2013 93, 579-586DOI: (10.1016/j.ajhg.2013.07.023) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 BAP31-Deficient Fibroblasts Have Abnormal Morphology (A) Immunohistochemistry performed on fibroblasts of two control individuals (C1 and C2), individual III.2 from family 1 (F1-III.2), individual IV.1 from family 2 (F2-IV.1), and individual III.1 from family 3 (F3-III.1) with an antibody against CALR (1:200, Stressgen ADI-SPA-600-F) (left panels) or HSPA5 (1:200, Abcam ab151269) (right panels). These images reveal the abnormal size and shape of BAP31-deficient fibroblasts compared with control fibroblasts. Cells were stained with DAPI for visualization of nuclear DNA. Scale bars represent 25 μm. (B) Quantification of the area and perimeter of control and affected individuals’ fibroblasts immunolabeled with CALR and shown in (A) demonstrates the statistically different values (∗p < 0.0001, Student’s t test) between the fibroblasts of the two control individuals and the three affected individuals. For each fibroblast, a region of interest delineated with ImageJ software defined the cell boundaries. The program measured the area and the perimeter expressed in square micrometers and micrometers, respectively. We measured the morphometric parameters of randomly selected fibroblasts (104 cells were analyzed for C1, 103 for C2, 80 for individual F1-III.2, 82 for individual F2-IV.1, and 60 for individual F3-III.1). Error bars represent the SEM. The American Journal of Human Genetics 2013 93, 579-586DOI: (10.1016/j.ajhg.2013.07.023) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 4 The Golgi Apparatus Is Disorganized in a Large Proportion of BAP31-Deficient Fibroblasts (A) Representative images show the abnormal structure of the Golgi apparatus in BAP31-deficient fibroblasts. The typical bean-shaped perinuclear Golgi structure observed in control fibroblasts was lost in a large proportion of BAP31-deficient fibroblasts, where it was replaced by small patches of GOLGA2-positive structures scattered in the cytoplasm. Immunohistochemistry was performed on fibroblasts from two control individuals (C1 and C2), individual III.2 from family 1 (F1-III.2), individual IV.1 from family 2 (F2-IV.1), and individual III.1 from family 3 (F3-III.1) with an antibody specific to GOLGA2 (green) (1:200, Sigma G7295). The fibroblasts were stained with DAPI for visualization of nuclear DNA. Scale bars represent 25 μm. (B) Percentage of fibroblasts showing a severely perturbed Golgi apparatus morphology in control samples and in the fibroblasts of the three affected individuals (∗p < 0.01, Chi-square test; 100 cells were counted in each of two experiments for each condition). (C) Representative electron-microscopy images reveal the ultrastructure of control fibroblasts (i and ii) and BAP31-deficient fibroblasts in individuals F1-III.2 (iii and iv), F2-IV.1 (v and vi), and F3-III.1 (vii and viii). The cells were washed, fixed in 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.4), postfixed in 1% osmium tetroxide, scraped, and centrifuged, and the pellet was dehydrated in graded alcohol solutions and embedded in SPURR low-viscosity medium. Ultrathin sections (50–60 nm) were counterstained with uranyl acetate and lead citrate before observation with a JEOL JEM1400 electron microscope at 80 kV. Images were obtained with a MegaView III camera (Soft Imaging System). The affected individuals’ fibroblasts contained an enlarged ER (black arrows) and numerous vesicles containing electron-dense material (asterisks) and lost the normal structure of their Golgi apparatus (white arrows in control fibroblasts). N = nucleus. Scale bars represent 2 μm (iv, v, and vi) or 1 μm (i, ii, iii, vii, and viii). The American Journal of Human Genetics 2013 93, 579-586DOI: (10.1016/j.ajhg.2013.07.023) Copyright © 2013 The American Society of Human Genetics Terms and Conditions