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XYLT1 Mutations in Desbuquois Dysplasia Type 2

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Presentation on theme: "XYLT1 Mutations in Desbuquois Dysplasia Type 2"— Presentation transcript:

1 XYLT1 Mutations in Desbuquois Dysplasia Type 2
Catherine Bui, Céline Huber, Beyhan Tuysuz, Yasemin Alanay, Christine Bole-Feysot, Jules G. Leroy, Geert Mortier, Patrick Nitschke, Arnold Munnich, Valérie Cormier-Daire  The American Journal of Human Genetics  Volume 94, Issue 3, Pages (March 2014) DOI: /j.ajhg Copyright © 2014 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Clinical Features of One DBQD Type 2 Subject with XYLT1 Mutation Individual 7 (family 6) at 12 months. Note the flat face, narrow thorax, short limbs (A) with hip dislocation, hyperlaxity of fingers (B), and deviation of toes (C). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Radiological Features of Two DBQD Type 2 Subjects with XYLT1 Mutations (A) Subject 1 (family 1) at 8 months. Note the monkey wrench appearance of the proximal femora, absence of upper femoral epiphyseal centers (a), knee dislocation (b), short long bones (c), and advanced carpal bone age (d). (B) Subject 4 (family 3) at 12 years of age. Note the scoliosis with irregular vertebral endplates (a), monkey wrench appearance of the proximal femora with short femoral necks, short and broad iliac wings (b), flat knee epiphyses (c), short metacarpals, and advanced carpal bone age and prominent wrist epiphyses (d). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Schematic Representation of the PG Biosynthesis
XT-I and XT-II participate in the initiation of the PG biosynthesis by transferring a Xyl to specific Ser residues of the core protein. Two Gal and one GlcUA will be sequentially added via the action of GalT-I, GalT-II, and GlcAT-I to form the common linker region. The addition of a GalNAc will then initiate the assembly of chondroitin-sulfate/dermatan-sulfate (CS/DS) chains while addition of a GlcNAc will initiate the synthesis toward heparan-sulfate/heparin (HS/Hep) chains. Mutations in genes involved in the assembly of the common linker region have been associated with several disorders, namely DBQD type 2 (XYLT1), Ehlers-Danlos progeroid syndrome, type 1 (B4GALT7), Ehlers-Danlos progeroid syndrome, type 2/spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1) (B3GALT6), and Larsen-like syndrome (B3GAT3). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Location of the Five XYLT1 Mutations
Organization of XYLT1 gene and protein with the two glycosyltransferase family 14 and xylosyltransferase domains. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

6 Figure 5 cDNA Level of XYLT1 in Controls and Two Cultured Individual Fibroblasts cDNA levels were normalized to GAPDH. Individuals p.Arg147∗ and p.Pro93Alafs∗69 are female aged 14 and male aged 23 years, respectively. Control 1 (female) and 2 (male) are aged 2.5 and 12 years, respectively. Control (black boxes) and individual (gray boxes) data are presented as box plots and are the mean of three independent experiments performed in quadruplate. ##p < 0.01, ###p < compared to control 1, ∗∗∗p < compared to control 2 by one-way ANOVA with Tukey’s post hoc test. Note that mutations in XYLT1 affect cDNA level of XYLT1. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

7 Figure 6 Sulfate Incorporation of Cellular Fractions in Controls and the Two Cultured Individual Fibroblasts in the Presence of 4-MUX or Vehicle The black (+4-MUX, 5 μM) and white (DMSO vehicle) bars represent the mean ± SEM of two independent experiments performed in triplicate. ∗∗∗p < when compared to the control 2 by one-way ANOVA with Tukey’s post hoc test. Note that XYLT1 mutations have an impact on the biosynthesis of cellular PGs in the two cultured individual fibroblasts. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

8 Figure 7 Gel Electrophoresis of Radiolabeled GAG Chains Extracted from Control 2 and the Two Cultured Individual Fibroblasts Media in the Presence 4-MUX or Vehicle For each sample, three lanes corresponding to nondigested (ND), digested by the Chondroitinase ABC (Ch), and digested by the Heparinases II and III (Hp) were loaded onto the gel and the volumes were adjusted to dpm values to visualize GAG profile and distribution. Control 2 (male) is aged 12. Note that mutations in XYLT1 change the distribution and profile of secreted PGs in the two cultured individual fibroblasts. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

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