Bobby G. Ng, Gege Xu, Nandini Chandy, Joan Steyermark, Deepali N

Slides:

Advertisements

Similar presentations

Previous Estimates of Mitochondrial DNA Mutation Level Variance Did Not Account for Sampling Error: Comparing the mtDNA Genetic Bottleneck in Mice and.

Advertisements

Connexin Mutations in Skin Disease and Hearing Loss David P. Kelsell, Wei-Li Di, Mark J. Houseman The American Journal of Human Genetics Volume 68, Issue.

Functional Analysis of the Neurofibromatosis Type 2 Protein by Means of Disease- Causing Point Mutations Renee P. Stokowski, David R. Cox The American.

Glucocorticoids Augment the Chemically Induced Production and Gene Expression of Interleukin-1α through NF-κB and AP-1 Activation in Murine Epidermal.

A Novel XPA Gene Mutation and its Functional Analysis in a Japanese Patient with Xeroderma Pigmentosum Group A Miki Tanioka, Arief Budiyant, Takahiro.

Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens Olivier.

FOG-1 represses GATA-1-dependent FcϵRI β-chain transcription: transcriptional mechanism of mast-cell-specific gene expression in mice by Keiko Maeda, Chiharu.

Splice-Site Mutations in the Axonemal Outer Dynein Arm Docking Complex Gene CCDC114 Cause Primary Ciliary Dyskinesia Alexandros Onoufriadis, Tamara Paff,

Proliferating Keratinocytes Are Putative Sources of the Psoriasis Susceptibility-Related EDA+(Extra Domain A of Fibronectin) Oncofetal Fibronectin Márta.

Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin Peter.

A Missense Mutation in PRPF6 Causes Impairment of pre-mRNA Splicing and Autosomal-Dominant Retinitis Pigmentosa Goranka Tanackovic, Adriana Ransijn,

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis Francesca Mattioli,

Tom Misteli, David L Spector Molecular Cell

Bobby G. Ng, Karl Hackmann, Melanie A. Jones, Alexey M

Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A

Structural and Functional Characterization of Factor H Mutations Associated with Atypical Hemolytic Uremic Syndrome Pilar Sánchez-Corral, David Pérez-Caballero,

IFN-γ Upregulates Expression of the Mouse Complement C1rA Gene in Keratinocytes via IFN-Regulatory Factor-1 Sung June Byun, Ik-Soo Jeon, Hyangkyu Lee,

Reliable Identification of Genomic Variants from RNA-Seq Data

Retinoic Acid Inhibits Downregulation of ΔNp63α Expression During Terminal Differentiation of Human Primary Keratinocytes Casimir Bamberger, Hartwig.

Volume 84, Issue 1, Pages (July 2013)

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

Antisense Masking of an hnRNP A1/A2 Intronic Splicing Silencer Corrects SMN2 Splicing in Transgenic Mice Yimin Hua, Timothy A. Vickers, Hazeem L. Okunola,

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia Thi Tuyet Mai.

Elisabeth Riedl, Yayoi Tada, Mark C. Udey

Volume 11, Issue 2, Pages (August 2018)

Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease Silvia Albert, Alejandro.

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

John D. Rioux, Valerie A. Stone, Mark J

RBPJ Mutations Identified in Two Families Affected by Adams-Oliver Syndrome Susan J. Hassed, Graham B. Wiley, Shaofeng Wang, Ji-Yun Lee, Shibo Li, Weihong.

A Homozygous Nonsense Mutation in Type XVII Collagen Gene (COL17A1) Uncovers an Alternatively Spliced mRNA Accounting for an Unusually Mild Form of Non-Herlitz.

A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John.

Nonsense mutation of EMX2 is potential causative for uterus didelphysis: first molecular explanation for isolated incomplete müllerian fusion Shan Liu,

Michael R. Knowles, Margaret W. Leigh, Lawrence E

Shiou-Hwa Jee Journal of Investigative Dermatology

A Novel XPA Gene Mutation and its Functional Analysis in a Japanese Patient with Xeroderma Pigmentosum Group A Miki Tanioka, Arief Budiyant, Takahiro.

Volume 20, Issue 5, Pages (August 2017)

Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria Barbara Kloeckener-Gruissem,

A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions Henna Tyynismaa,

Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome Sarah B. Pierce, Tom Walsh, Karen.

Human Elastase 1: Evidence for Expression in the Skin and the Identification of a Frequent Frameshift Polymorphism Ulvi Talas, John Dunlop, Sahera Khalaf,

Erratum The American Journal of Human Genetics

Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang,

Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome Fuxi Zhu, Fengsong Wang, Xiaoyu Yang, Jingjing Zhang, Huan Wu, Zhou.

Katsiaryna Belaya, Sarah Finlayson, Clarke R

Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

Homozygous Mutations in the 5′ Region of the JUP Gene Result in Cutaneous Disease but Normal Heart Development in Children Rita M. Cabral, Lu Liu, Carol.

Identification of FOXP2 Truncation as a Novel Cause of Developmental Speech and Language Deficits Kay D. MacDermot, Elena Bonora, Nuala Sykes, Anne-Marie.

Correct mRNA Processing at a Mutant TT Splice Donor in FANCC Ameliorates the Clinical Phenotype in Patients and Is Enhanced by Delivery of Suppressor.

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

Annemieke Aartsma-Rus, Anneke A. M. Janson, Wendy E

Tom Misteli, David L Spector Molecular Cell

ST3GAL3 Mutations Impair the Development of Higher Cognitive Functions

A Lack of Birbeck Granules in Langerhans Cells Is Associated with a Naturally Occurring Point Mutation in the Human Langerin Gene Pauline Verdijk, Remco.

Direct effects of dexamethasone on human podocytes

Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans Ranad Shaheen, Hanan E. Shamseldin, Catrina M.

Regulation of Tissue Factor in Microvascular Dermal Endothelial Cells

Janet A. Fairley, Chang Ling Fu, George J. Giudice

Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth

Arun Kumar, Satish C. Girimaji, Mahesh R. Duvvari, Susan H. Blanton

GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome Amy J. LaCroix, Deborah Stabley, Rebecca.

Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein GPSM2 as the Cause of Nonsyndromic Hearing Loss DFNB82

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

Mutations in PTPRQ Are a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB84 and Associated with Vestibular Dysfunction Margit Schraders,

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy Hanan E. Shamseldin,

Hannah R. Elliott, David C. Samuels, James A. Eden, Caroline L

Identification of a New Splice Form of the EDA1 Gene Permits Detection of Nearly All X- Linked Hypohidrotic Ectodermal Dysplasia Mutations Alex W. Monreal,

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis Francesca Mattioli,

Identification and Functional Analysis of ZIC3 Mutations in Heterotaxy and Related Congenital Heart Defects Stephanie M. Ware, Jianlan Peng, Lirong Zhu,

Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V Anthony Antonellis, Rachel E. Ellsworth,

Presentation transcript:

Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation Bobby G. Ng, Gege Xu, Nandini Chandy, Joan Steyermark, Deepali N. Shinde, Kelly Radtke, Kimiyo Raymond, Carlito B. Lebrilla, Ali AlAsmari, Sharon F. Suchy, Zöe Powis, Eissa Ali Faqeih, Susan A. Berry, David F. Kronn, Hudson H. Freeze The American Journal of Human Genetics Volume 102, Issue 1, Pages 188-195 (January 2018) DOI: 10.1016/j.ajhg.2017.12.009 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of FUT8 Pathogenic Variants in Three Unrelated Families (A) Schematic of the FUT8 dependent α1,6 fucosyltransferase enzymatic reaction creating a core fucose motif. (B) Pedigrees showing FUT8 pathogenic variants and segregation in families 0448, 0459, and 0464. (C) Schematic of Human FUT8 with the relative positions of each pathogenic variant on mRNA (GenBank: NM_178155.2) and protein level (Uniprot: Q9BYC5). The American Journal of Human Genetics 2018 102, 188-195DOI: (10.1016/j.ajhg.2017.12.009) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Effect of FUT8 Pathogenic Variants on Protein Expression and mRNA Splicing (A) Western blot analysis of FUT8 protein in fibroblast from three controls, CDG-0448 and CDG-0459 showing loss of FUT8 protein expression. Two different monoclonal antibodies with separate epitopes were used to detect human FUT8 protein. The first monoclonal anti-FUT8 recognizes an epitope within amino acids 31–230 and was used at a 1:500 dilution and (Santa Cruz Biotechnology, sc-271244), while the second has an epitope within amino acids 276–575 and was used at a 1:2,000 dilution (Proteintech 66118-1-Ig). (B) Splicing analysis was performed using primers spanning exon 8 to exon 10 of FUT8 mRNA and determined that the c.1259+5G>T, found in CDG-0459, produced an abnormal transcript lacking exon 9. Two independent RNA preparations are shown for CDG-0459. The American Journal of Human Genetics 2018 102, 188-195DOI: (10.1016/j.ajhg.2017.12.009) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Characterization of N-Glycans from Whole Serum using LC-MS LC-MS chromatograms for control, CDG-0448, CDG-0459, and CDG-0464 showing the loss of multiple core fucosylated N-glycans (green shade). Unlike the other two affected individuals, CDG-0464 also had an absence of non-fucosylated neutral glycans (orange shade), which is not due to the loss of FUT8. The American Journal of Human Genetics 2018 102, 188-195DOI: (10.1016/j.ajhg.2017.12.009) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 Characterization of N-Glycans from Primary Fibroblasts using LC-MS and Flow Cytometry LC-MS chromatograms for Control, CDG-0448, and CDG-0459 showing the loss of multiple fucosylated N-glycans (green shade). The control used, GM-05381, is representative of three different control lines (GM-00038, GM-03348, GM-05381). The American Journal of Human Genetics 2018 102, 188-195DOI: (10.1016/j.ajhg.2017.12.009) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 5 Lectin Analysis of Cell Surface Core Fucosylated N-Glycans (A) Flow cytometry was used to evaluate the cell surface binding of FITC-LcH (Lens culinaris agglutinin) in the two affected individuals and in a representative control culture and showed reduced lectin staining in both affected individuals. (B) Flow cytometry analysis of cell surface FITC-PSA (Pisum sativum agglutinin) in the two affected individuals and in a representative control culture and showed reduced lectin staining in both affected individuals. GM-03348 is representative of three different control lines (GM-00038, GM-03348, GM-05381). The American Journal of Human Genetics 2018 102, 188-195DOI: (10.1016/j.ajhg.2017.12.009) Copyright © 2017 American Society of Human Genetics Terms and Conditions