RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome Lina Basel-Vanagaite, Ofer Sarig, Dov Hershkovitz, Dana Fuchs-Telem,

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Date of download: 5/29/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Reduced Aquaporin 4 Expression in the Muscle Plasma.

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RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome Lina Basel-Vanagaite, Ofer Sarig, Dov Hershkovitz, Dana Fuchs-Telem, Debora Rapaport, Andrea Gat, Gila Isman, Idit Shirazi, Mordechai Shohat, Claes D. Enk, Efrat Birk, Jürgen Kohlhase, Uta Matysiak-Scholze, Idit Maya, Carlos Knopf, Anette Peffekoven, Hans- Christian Hennies, Reuven Bergman, Mia Horowitz, Akemi Ishida-Yamamoto, Eli Sprecher The American Journal of Human Genetics Volume 85, Issue 2, Pages 254-263 (August 2009) DOI: 10.1016/j.ajhg.2009.07.001 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Phenotype (A and B) Facial appearance of patients II-4 (A) and II-5 (B). Note age-dependant worsening of the sagging skin phenotype. (C) Mild ichthyosis can be seen in patient II-4. (D) Skull radiographs of a normal individual (left) and of a patient (right). (E) Short and sparse hair can be seen in patient II-5. (F) Severe kyphoscoliosis can be seen in patient II-4. (G) Irregularly placed teeth and gingival hypertrophy can be seen in patient II-4. (H) Panoramic X-ray of the oral cavity in patient II-5, demonstrating unerupted wisdom and upper canine teeth. The American Journal of Human Genetics 2009 85, 254-263DOI: (10.1016/j.ajhg.2009.07.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Pathological Features (A–C) Histopathological examination of a skin biopsy obtained from patient II-5 (A) revealed a normal epidermis, with a striking absence of elastic fibers in the papillary dermis (C) as opposed to the reticular dermis (B). (D) A higher magnification demonstrates almost complete absence of oxytalin fibers. (E and F) Von Giesen (E) and Masson Trichrome (F) staining demonstrates a normal structure of elastic and collagen fibers in the reticular dermis. (G) Transmission electron microscopy of dermal elastic fibers demonstrates diminished microfibrillar component at the periphery of elastic fibers (arrows) (e, elastic fiber; c, collagen fibers). (H and I) Immunohistochemical staining demonstrates decreased expression of fibulin-5 in the patient dermis (I) as compared with normal skin (H). The American Journal of Human Genetics 2009 85, 254-263DOI: (10.1016/j.ajhg.2009.07.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation Identification (A) Relative position of the disease interval and of the RIN2 gene on 20p11.21-p11.23. (B) Relative expression of RIN2 in patient (P1-2) and control (C1-4) fibroblasts. (C) Sequence analysis reveals a homozygous C deletion at cDNA position 1731 of the RIN2 gene (lower panel). The wild-type sequence is given for comparison (upper panel). (D) PCR-RFLP analysis confirms segregation of the mutation in the family. PCR amplification was performed as described in the text. Affected patients display a homozygous 183 bp fragment, healthy individuals show a 152 bp fragment only, but the two fragments are found in heterozygous carriers of the mutation. The American Journal of Human Genetics 2009 85, 254-263DOI: (10.1016/j.ajhg.2009.07.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 Consequences of the c.1731delC Mutation in RIN2 (A) Quantitative reverse transcriptase-PCR was performed on mRNA samples extracted from skin biopsies of patients (P1, P2) and healthy individuals (C1, C2). (B) Protein was extracted from fibroblast cell cultures established from two MACS syndrome patients (P1, P2) and a control healthy individual (C) and was immunoblotted against anti-RIN2. Membranes were reblotted with anti-β-actin antibodies to control for protein loading (insert). Densitometry results are provided as arbitrary units ± SD. The American Journal of Human Genetics 2009 85, 254-263DOI: (10.1016/j.ajhg.2009.07.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 5 Ultrastuctural Consequences of RIN2 Deficiency (A and B) Electron microscopy demonstrates numerous vacuoles (red asterisks) closely associated with the stacks of the Golgi apparatus in patient fibroblasts (B) as compared with normal fibroblasts (A). (C and D) Numerous similar vacuoles were see in human telomerase reverse transcriptase (hTERT)-transformed fibroblasts transfected with a RIN2-specific siRNA (Sigma Oligo no. 3960234, 3960235, 3960236, 3960237) (D) as compared with the same cells transfected with a control irrelevant siRNA (C). (E) We quantitatively compared the number of vacuoles per cell (n = 30) in patient (blue) versus control (red) fibroblasts (PF) and in hTERT-transformed fibroblasts (HTF) transfected with a RIN2-specific siRNA (blue) or a control siRNA (red). p values were calculated by a standard t test (asterisk indicates p < 0.0001). The American Journal of Human Genetics 2009 85, 254-263DOI: (10.1016/j.ajhg.2009.07.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 6 The Kinetics of Transferrin Recycling Are Normal in Rin2-Deficient Fibroblasts (A) RIN2-deficient primary fibroblasts, derived from two patients (FACH and FMCH), were transformed with SV40 T-large antigen (FACHT and FMCHT). FACHT and FMCHT cells, as well as normal cells (F572T), were starved for 30 min, incubated with biotin-conjugated transferrin for 15 min, and chased for the indicated times. Equal amounts of protein lysates were subjected to SDS-PAGE, blotted, and interacted with streptavidin/HRP. Blots were reprobed with anti-ERK as a loading control. Data are representative of two independent experiments. (B) Densitometry was used to quantitate the kinetics of biotinylated transferrin internalization and recycling. To normalize the results, we divided intensity of the transferrin band at each lane by the intensity of the total ERK (ERK1 and ERK2). The value obtained for the pulse time was considered as 100%. The results represent the mean of two independent experiments. Abbreviations are as follows: Tf, transferrin; Rin2-, RIN2-deficient cells. The American Journal of Human Genetics 2009 85, 254-263DOI: (10.1016/j.ajhg.2009.07.001) Copyright © 2009 The American Society of Human Genetics Terms and Conditions