Mutations in the ZNF41 Gene Are Associated with Cognitive Deficits: Identification of a New Candidate for X-Linked Mental Retardation Sarah A. Shoichet,

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Mutations in the ZNF41 Gene Are Associated with Cognitive Deficits: Identification of a New Candidate for X-Linked Mental Retardation Sarah A. Shoichet, Kirsten Hoffmann, Corinna Menzel, Udo Trautmann, Bettina Moser, Maria Hoeltzenbein, Bernard Echenne, Michael Partington, Hans van Bokhoven, Claude Moraine, Jean-Pierre Fryns, Jamel Chelly, Hans-Dieter Rott, Hans-Hilger Ropers, Vera M. Kalscheuer The American Journal of Human Genetics Volume 73, Issue 6, Pages 1341-1354 (December 2003) DOI: 10.1086/380309 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 A, Ideograms depicting normal chromosomes X and 7 and their derivatives der(X) and der(7). Patient metaphase chromosomes were used for FISH of X-chromosomal breakpoint-spanning cosmid clone LAII14H20 with signals on the normal X and split signals on der(X) and der(7) as indicated (B), and chromosome 7 breakpoint-spanning BAC clone RP11-196D18 (GenBank accession number AC069285) with signals on the normal 7 and split signals on der(7) and der(X) as indicated (C). The American Journal of Human Genetics 2003 73, 1341-1354DOI: (10.1086/380309) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 A, Southern blot of patient (P) and control (C) genomic DNA probed with a PCR product corresponding to nucleotides 9529–10112 of clone RP11-83I24. Aberrant fragments specific to patient DNA (black arrows) in HincII (left) and EcoRI (right) digests correspond to sizes of ∼10 kb and ∼1 kb, respectively. B, Sequence of the breakpoint region indicating (in large type) the three nucleotides common to both chromosome X and chromosome 7. The American Journal of Human Genetics 2003 73, 1341-1354DOI: (10.1086/380309) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 A, Schematic diagram (not to scale) indicating the exon-intron structure of ZNF41 relative to the breakpoint location. Arrows indicate location of primers used for RT-PCR analysis. B, RT-PCR analysis by use of ZNF41 primers spanning the breakpoint. ZNF41 product corresponds to nucleotides 407–702 of GenBank accession number NM_007130. Amplification of HPRT served as a control. A plus sign (+) indicates with reverse transcriptase; a minus sign (−) indicates mock reaction. The American Journal of Human Genetics 2003 73, 1341-1354DOI: (10.1086/380309) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 A, Pedigree of family P13, with sequence corresponding to the proline→leucine mutation (left to right): unrelated control individual, mother (II:1), index patient (III:2), and brother of the index patient (III:1). For the potentially affected female cousin (individual III-4) (indicated with an asterisk [*]), no clinical data are available. Affected nucleotides are indicated with black arrows. B, Pedigree for family P42, with sequence chromatograms indicating the splice-site mutation in affected individuals (left to right): father (I:1), mother (I:2), index patient (II:1), and mildly affected sister (II:2). Uppercase letters indicate coding sequence; affected nucleotides are indicated with black arrows. The American Journal of Human Genetics 2003 73, 1341-1354DOI: (10.1086/380309) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 5 A, RT-PCR for ZNF41.3 in male control (CON 1), female control (CON 2), and patient (PAT) lymphoblastoid cell lines. The schematic diagram below the cell lines (not to scale) indicates the exonic structure of both normal and predicted aberrant ZNF41.3 transcripts, with respect to the predominant transcript variant ZNF41.1, and the respective locations of primers F2 and R1 (specific for variants 41.3 and 41.6) used for amplification. Shaded regions indicate predicted coding sequence; patterns differentiate between reading frames. The adenine→cytidine intronic splice-site mutation in the patient is underlined and indicated in bold typeface. B, RT-PCR for the novel transcript variant ZNF41.9 in the same samples. As in section A, the schematic diagram indicates the intronic mutation, the structure of ZNF41.9 relative to the predominant transcript ZNF41.1, the location of primers F1 and R1 used for amplification, and the predicted coding sequences of the resulting transcript variants. Amplification of HPRT served as a control. A plus sign (+) indicates with reverse transcriptase; a minus sign (−) indicates mock reaction. The American Journal of Human Genetics 2003 73, 1341-1354DOI: (10.1086/380309) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 6 Northern blot hybridization of ZNF41, by use of a probe corresponding to nucleotides 621–1099 of ZNF41 transcript variant 1. A, Adult tissues (left to right): heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. B, Fetal tissues (left to right): brain, lung, liver, and kidney. C, Adult brain structures (left to right): amygdala, caudate nucleus, corpus callosum, hippocampus, whole brain, substantia nigra, and thalamus. Black arrowheads highlight the presence of a novel 6-kb transcript. Actin (A and C) or GAPDH (B) served as controls for RNA loading. The American Journal of Human Genetics 2003 73, 1341-1354DOI: (10.1086/380309) Copyright © 2003 The American Society of Human Genetics Terms and Conditions