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1.
Figure 3

Figure 3. From: Disruption of an EHMT1-Associated Chromatin-Modification Module Causes Intellectual Disability.

An Epigenetic Network Underlying KSS
Functional studies indicate that genes implicated in KSS occur in a common chromatin-regulating module. This evidence comes from investigation of direct protein-protein interactions (solid lines) and from genetic interaction studies with Drosophila melanogaster (dashed lines). Green dashed lines indicate a synergistic interaction, and red dashed lines indicate an antagonistic interaction. It has been demonstrated in this study that Drosophila EHMT interacts genetically with sba/MBD5, trr/MLL3, and EcR/NR1I3 (GI1, GI2, and GI3, respectively). Previously, genetic and physical interactions between trr and EcR (GI4 and DPI1, respectively), as well as physical association between SMARCB1 and MLL3 (DPI2), have been demonstrated. 32,42

Tjitske Kleefstra, et al. Am J Hum Genet. 2012 July 13;91(1):73-82.
2.
Figure 1

Figure 1. From: Disruption of an EHMT1-Associated Chromatin-Modification Module Causes Intellectual Disability.

Clinical Photographs and Mutation Information
(A–D) Photographs of individuals with KSS and chromatograms comparing individuals with KSS to parents and/or siblings indicate de novo occurrence for the four probably pathogenic mutations identified. Mutations are highlighted in yellow.
(A) KS113 with MLL3 mutation c.4441C>T. Reverse-strand sequences of individual KS113, the mother, and two healthy sisters are shown. Note the midface hypoplasia, synophrys, upward slant of palpebral fissures, and everted lower lip.
(B) KS47 with SMARCB1 mutation c.110G>A, which is not present in the parental DNA. Note the midface hypoplasia, upward slant of the eyes, and tongue protrusion.
(C) KS78 with MBD5 mutation c.150del, which is not present in the parental DNA. A reverse-strand sequence is shown. Note the synophrys, upward slant of palpebral fissures, upturned nose with broad tip, full lips, and everted lower lip.
(D) KS220 with NR1I3 mutation c.740T>C, which is not present in the parental DNA. Reverse-strand sequences are shown. Note the midface hypoplasia, short upturned nose, everted lower lip, and pointed chin.
(E) Four KSS individuals (KS1, KS2, KS245, and KS21) with previously published 6,7,10 EHMT1 defects show a close resemblance of facial characteristics to the four individuals in (A)–(D).

Tjitske Kleefstra, et al. Am J Hum Genet. 2012 July 13;91(1):73-82.
3.
Figure 2

Figure 2. From: Disruption of an EHMT1-Associated Chromatin-Modification Module Causes Intellectual Disability.

Drosophila Orthologs of MBD5, MLL3, and NR1I3 Interact Genetically with EHMT
(A) The morphology of the wild-type Drosophila wing is defined by five longitudinal veins (L1–L5) and the anterior and posterior cross veins (a-cv and p-cv).
(B) Tissue-specific overexpression of UAS-EHMT in the Drosophila wing with the use of MS1096-Gal4 causes ectopic wing vein formation between L2 and L3 in 91% of wings and between the p-cv and L5 in 88% of wings (arrows).
(C) Expression of sba/MBD5 with UAS-sba in the fly wing induced mild ectopic wing vein formation posterior to L5 with about 50% penetrance (arrow).
(D) In combination with UAS-EHMT, this phenotype was severely enhanced, resulting in a highly consistent disruption of normal L5 formation and a massive increase in ectopic vein formation between L2 and L3 in all wings examined (arrows).
(E) RNAi-mediated knockdown of trr/MLL3 by induced expression of an inverted repeat (IR) producing double-stranded RNA homologous to trr (UAS-trrIR) caused mild loss of wing vein L5 and a slight upward curvature of the wing.
(F) In combination with UAS-EHMT, UAS-trrIR induced pupal lethality caused by the formation of black necrotic tissue in the developing wing (arrowhead). Identical results were obtained with two individual UAS-trrIR lines (Table S7). Data is shown for UAS-trrIR1.
(G) EHMT-induced ectopic wing vein formation between L2 and L3 is variable in severity and can be quantified accordingly into wild-type, mild, medium, and strong.
(H) The effect of UAS-EHMT expression on ectopic vein formation in this region is rescued by RNAi-mediated knockdown of EHMT with the use of UAS-EHMTIR1. Similar results were obtained with two other EHMT RNAi constructs (Table S7). In contrast, CG5026/MTMR9 knockdown had no effect on the EHMT-induced phenotype, as observed with three individual UAS-CG5026IR lines (Table S7). Loss-of-function mutations in EcR were able to rescue EHMT-mediated ectopic vein formation, indicating that EcR is required for this EHMT-induced phenotype. Similar data were obtained with the EcRQ50st allele, the EcRM554fs allele, and two EcR RNAi lines (Table S7). Overexpression of EcR isoform A caused very mild induction of ectopic vein formation. However, in combination with UAS-EHMT, UAS-EcR-A strongly enhanced EHMT-induced ectopic vein formation. Similar results were obtained by overexpression of the other EcR isoforms, B1 and B2.

Tjitske Kleefstra, et al. Am J Hum Genet. 2012 July 13;91(1):73-82.

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