A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

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A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana Kariminejad, Farkhondeh Behjati, Andreas Tzschach, Hossein Najmabadi, Hans Hilger Ropers, Andreas Walter Kuss The American Journal of Human Genetics Volume 82, Issue 5, Pages 1158-1164 (May 2008) DOI: 10.1016/j.ajhg.2008.03.018 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree and Facial Aspects of Affected Family Members Filled symbols indicate severe MR, and three-quarter-filled symbols depict moderate MR. The American Journal of Human Genetics 2008 82, 1158-1164DOI: (10.1016/j.ajhg.2008.03.018) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Results of Parametric Linkage Analysis with Merlin Software A single significant peak (LOD score 6.26) was observed on chromosome 8p22 between rs613566 and rs11203893. The American Journal of Human Genetics 2008 82, 1158-1164DOI: (10.1016/j.ajhg.2008.03.018) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Copy-Number Analysis and Haplotyping of MR Patients (A) Results of nonpaired DNA copy-number analysis (CNAG2 tool for copy-number variations): Copy-number state (upper) and log2 ratios (lower) for Nsp-array SNP markers located inside the first ∼30 Mb of chromosome 8 are displayed for one individual per branch, showing a 120 Kbp homozygous deletion of 8p22 comprising the first exon of TUSC3. (B) The markers bordering the deletion as well as the first and last two deleted markers are shown, revealing that all the affected members are homozygous for the same haplotype, whereas parents and healthy sibs are heterozygous carriers. The American Journal of Human Genetics 2008 82, 1158-1164DOI: (10.1016/j.ajhg.2008.03.018) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Deletion Encompassing the First Exon of TUSC3 in MR Patients (A) Schematic representation of TUSC3: Arrowheads represent exons, and gray boxes mark the positions of simple tandem repeats that could be causatively involved in the genesis of the deletion. The positions of the borders of the 121,595 bp deletion (based on NCBI Build 36.1) are indicated. The sequence chromatogram shows part of the PCR amplicon covering the junction of the deletion borders. (B) Cosegregation analysis by PCR: Results of a deletion-specific PCR (I) and a deletion-spanning PCR (II) are shown for all the available family members. All homozygous carriers show only amplification of the junction fragment (II), heterozygous carriers show both amplicons, and noncarriers show only amplicon I. (C) RT-PCR results from an experiment with cDNA derived from RNA preparations of one patient (IV:5) and one control lymphoblastoid cell line sample. With a sequence of primer pairs specific for amplicons covering two to three consecutive exons each, the complete TUSC3 transcript was detected in the control but could not be amplified from patient cDNA. The results of an agarose gel electrophoresis of 5 μl from a 25 μl RT-PCR reaction (primers and conditions are available upon request) are shown. Patient and control products for a specific amplicon (the exons covered by each amplicon are indicated) were loaded on neighboring lanes in ascending order of the amplified exons. As positive control, a PCR specific for the X-chromosomal HUWE1 gene (MIM 300697) was performed (lane 15 and 16). Filled squares represent the patient and open squares the control, “B” marks the lane loaded with the negative control, and “M” indicates the marker lane (HyperLadder IV, Bioline). The American Journal of Human Genetics 2008 82, 1158-1164DOI: (10.1016/j.ajhg.2008.03.018) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 5 Schematic Representations of Predicted Functional Domains in the TUSC3 Gene Product The 348 amino acid TUSC3 protein is shown as an open box. Different functional domains are indicated. Differently colored shading marks their extent and position within the protein. The deletion encompasses the first 46 amino acids and is indicated by gray shading. The American Journal of Human Genetics 2008 82, 1158-1164DOI: (10.1016/j.ajhg.2008.03.018) Copyright © 2008 The American Society of Human Genetics Terms and Conditions