Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2 Celia Zazo Seco, Luciana.

Slides:

Advertisements

Similar presentations

Mutations of the Gene Encoding Otogelin Are a Cause of Autosomal-Recessive Nonsyndromic Moderate Hearing Impairment Margit Schraders, Laura Ruiz-Palmero,

Advertisements

Mutations in OTOGL, Encoding the Inner Ear Protein Otogelin-like, Cause Moderate Sensorineural Hearing Loss Kemal O. Yariz, Duygu Duman, Celia Zazo Seco,

Hongda Li, Stephanie L. Bielas, Maha S

Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal- Recessive Nonsyndromic Hearing Impairment Margit Schraders, Kwanghyuk Lee, Jaap.

A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia Joris van der Heijden, MSc, Judy Geissler, Edwin.

Mutations in CDC14A, Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness Sedigheh.

Ilse Feenstra, Lisenka E. L. M. Vissers, Ronald J. E

Mutations in AGBL1 Cause Dominant Late-Onset Fuchs Corneal Dystrophy and Alter Protein-Protein Interaction with TCF4 S. Amer Riazuddin, Shivakumar Vasanth,

NR2F1 Mutations Cause Optic Atrophy with Intellectual Disability

A Nonsense Mutation in the Human Homolog of Drosophila rogdi Causes Kohlschutter– Tonz Syndrome Adi Mory, Efrat Dagan, Barbara Illi, Philippe Duquesnoy,

Volume 14, Issue 5, Pages (March 2004)

Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta Walid El-Sayed, David A. Parry, Roger C. Shore,

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,

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

Mutations in TPRN Cause a Progressive Form of Autosomal-Recessive Nonsyndromic Hearing Loss Yun Li, Esther Pohl, Redouane Boulouiz, Margit Schraders,

GRACILE Syndrome, a Lethal Metabolic Disorder with Iron Overload, Is Caused by a Point Mutation in BCS1L Ilona Visapää, Vineta Fellman, Jouni Vesa, Ayan.

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I Christian Guelly, Peng-Peng.

TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy Antonio Falace, Fabia Filipello, Veronica La Padula, Nicola.

Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization Yohann Jourdy, Alexandre Janin, Mathilde Fretigny, Anne Lienhart, Claude.

De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability

Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal- Recessive Osteogenesis Imperfecta Jutta Becker, Oliver Semler, Christian.

Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects Konstantinos Nikopoulos, Pietro Farinelli, Basilio.

Exome Sequencing Identifies SLC24A5 as a Candidate Gene for Nonsyndromic Oculocutaneous Albinism Ai-Hua Wei, Dong-Jie Zang, Zhe Zhang, Xuan-Zhu Liu,

Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3 Tarja Joensuu, Riikka Hämäläinen, Bo Yuan, Cheryl Johnson, Saara.

Javier A. Couto, August Y. Huang, Dennis J. Konczyk, Jeremy A

Evangelia S. Panagiotou, Carla Sanjurjo Soriano, James A

Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease Alberto Auricchio, Paola.

CNNM2, Encoding a Basolateral Protein Required for Renal Mg2+ Handling, Is Mutated in Dominant Hypomagnesemia Marchel Stuiver, Sergio Lainez, Constanze.

The c.1364C>A (p.A455E) Mutation in the CFTR Pseudogene Results in an Incorrectly Assigned Carrier Status by a Commonly Used Screening Platform Kristin.

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism

Mutations in TRIOBP, Which Encodes a Putative Cytoskeletal-Organizing Protein, Are Associated with Nonsyndromic Recessive Deafness Saima Riazuddin, Shaheen.

Terminal Osseous Dysplasia Is Caused by a Single Recurrent Mutation in the FLNA Gene Yu Sun, Rowida Almomani, Emmelien Aten, Jacopo Celli, Jaap van der.

DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal- Dominant Robinow Syndrome Janson White, Juliana F. Mazzeu, Alexander Hoischen,

Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy Kornelia Neveling,

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang.

PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy.

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.

Christian Gilissen, Heleen H

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

Mutations in MED12 Cause X-Linked Ohdo Syndrome

Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang.

Yavuz Bayram, Janson J. White, Nursel Elcioglu, Megan T

TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy Antonio Falace, Fabia Filipello, Veronica La Padula, Nicola.

Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility Elma El Khouri, Lucie Thomas, Ludovic Jeanson,

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

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

Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization Yohann Jourdy, Alexandre Janin, Mathilde Fretigny, Anne Lienhart, Claude.

DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal- Dominant Robinow Syndrome Janson J. White, Juliana F. Mazzeu, Alexander.

PEX3 Is the Causal Gene Responsible for Peroxisome Membrane Assembly–Defective Zellweger Syndrome of Complementation Group G Kamran Ghaedi, Masanori.

Nonsense Mutations in SMPX, Encoding a Protein Responsive to Physical Force, Result in X-Chromosomal Hearing Loss Antje K. Huebner, Marta Gandia, Peter.

Hirokatsu Yanagihori, Noritaka Oyama, Koichiro Nakamura, Fumio Kaneko

Volume 5, Issue 6, Pages (November 2012)

Hongda Li, Stephanie L. Bielas, Maha S

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

Identification of 51 Novel Exons of the Usher Syndrome Type 2A (USH2A) Gene That Encode Multiple Conserved Functional Domains and That Are Mutated in.

Uma B. Karadge, Minja Gosto, Matthew L. Nicotra Current Biology

Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy Hirotomo Saitsu,

MPZL2, Encoding the Epithelial Junctional Protein Myelin Protein Zero-like 2, Is Essential for Hearing in Man and Mouse Mieke Wesdorp, Silvia Murillo-Cuesta,

Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain Clare V. Logan,

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,

Loss of SUFU Function in Familial Multiple Meningioma

Gain-of-Function Mutation of KIT Ligand on Melanin Synthesis Causes Familial Progressive Hyperpigmentation Zhi-Qiang Wang, Lizhen Si, Quan Tang, Debao.

A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System John F. Staropoli, Amel Karaa, Elaine T. Lim,

Asaf Ta-Shma, Tahir N. Khan, Asaf Vivante, Jason R

Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L

A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes Autosomal-Recessive Hearing Impairment Isabelle Schrauwen, Sarah Helfmann, Akira Inagaki,

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

Presentation transcript:

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2 Celia Zazo Seco, Luciana Serrão de Castro, Josephine W. van Nierop, Matías Morín, Shalini Jhangiani, Eva J.J. Verver, Margit Schraders, Nadine Maiwald, Mieke Wesdorp, Hanka Venselaar, Liesbeth Spruijt, Jaap Oostrik, Jeroen Schoots, Jeroen van Reeuwijk, Stefan H. Lelieveld, Patrick L.M. Huygen, María Insenser, Ronald J.C. Admiraal, Ronald J.E. Pennings, Lies H. Hoefsloot, Alejandro Arias-Vásquez, Joep de Ligt, Helger G. Yntema, Joop H. Jansen, Donna M. Muzny, Gerwin Huls, Michelle M. van Rossum, James R. Lupski, Miguel Angel Moreno-Pelayo, Henricus P.M. Kunst, Hannie Kremer The American Journal of Human Genetics Volume 97, Issue 5, Pages 647-660 (November 2015) DOI: 10.1016/j.ajhg.2015.09.011 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Families Affected by KITLG Mutations (A) Pedigree of family W09-1628, affected by NS-UHL/AHL. Asterisks indicate individuals who were genotyped with HumanOmniExpress BeadChip arrays. For privacy reasons, the genotype for the c.286_303delinsT variant has not been indicated for unaffected individuals, except for those with affected offspring. Abbreviations are as follows: M, mutant allele c.286_303delinsT; +, the wild-type allele; ?, unclear affection status. (B) Pedigree of family S1489, affected by NS-AHL. Abbreviations are as follows: M, the c.200_202del variant; +, the wild-type allele. (C) Pedigree of family 12-01744, affected by WS2. Abbreviations are as follows: M, the variant c.310C>G; +, the wild-type allele; ?, unclear affection status. The American Journal of Human Genetics 2015 97, 647-660DOI: (10.1016/j.ajhg.2015.09.011) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Pure Tone Audiometry in Families Affected by KITLG Mutations (A) Pure tone audiograms for family-W09-1628 individuals with UHL (III:5) and AHL (V:6). (B) Pure tone audiograms for family S1489, affected by AHL. (C) Pure tone audiograms for family 12-01744, affected by WS2. Abbreviations are as follows: R, right ear; L, left ear; P95, thresholds according to the P95 of presbyacusis (ISO 7029:1984).14 The American Journal of Human Genetics 2015 97, 647-660DOI: (10.1016/j.ajhg.2015.09.011) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Eye and Skin Hypopigmentation Phenotypes in Family 12-01744, Affected by WS2 (A) Heterochromia iridis in the index case, individual II:1. (B) Signs of heterochromia iridis in his mother (I:2). (C) A hypopigmented, sharply demarcated macule on the thorax of individual II:1 and (D) on the upper arm. A nummular, sharply demarcated hyperpigmented macula at the back, detected by a Wood’s lamp. The American Journal of Human Genetics 2015 97, 647-660DOI: (10.1016/j.ajhg.2015.09.011) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Genetic Defects Underlying UHL and AHL and Schematic Representation of the Genomic Structure of KITLG and of the Encoded KITLG Isoforms (A) Electropherograms of pCR4-topo clones representing the wild-type and c.286_303delinsT alleles of KITLG exon 4 of individual IV:1 (family W09-1628). (B) Electropherograms of pCR4-topo clones representing the wild-type and c.200_202del alleles of KITLG exon 4 of individual III:1 (family S1489). (C) Partial nucleotide sequences of KITLG exon 4 of case II:1 of family 12-01744. The mutated nucleotide is marked by an arrowhead. GenBank: NM_003994.5 and NM_000899.4 were used as reference sequences. (D) Exon 6 is alternatively spliced. The yellow dots represent the gain-of-function mutations c.98C>T, c.100A>C, and c.107A>G, causative of familial hyper- and hypopigmentation syndromes. The green and red dots represent the mutations identified to be causative of NS-UHL/AHL in the present study. The white dot represents the mutation identified in a family with WS2. All depicted variants affect the KIT ligand domain of both the soluble and transmembrane isoforms of KITLG. Abbreviation is as follows: WT, wild-type. The American Journal of Human Genetics 2015 97, 647-660DOI: (10.1016/j.ajhg.2015.09.011) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 5 Effect of KITLG Mutations on Subcellular Localization and Excretion of the Transmembrane and Soluble KITLG Isoforms, Respectively (A) WGA staining of NIH 3T3 cells transfected with constructs encoding the FLAG-tagged wild-type, p.His67_Cys68delinsArg, and p.Leu104Val transmembrane isoform of KITLG. Cells were incubated with anti-FLAG antibodies and Alexa-488-conjugated goat anti-mouse (left column), and WGA Texas Red-X is visualized in the middle column. In the right column, the signals of the left and middle columns are merged. Co-localization of WGA with wild-type and p.Leu104Val KITLG was observed at the cell membrane but not with p.His67_Cys68delinsArg KITLG. WGA (red) and KITLG (green) fluorescence intensity profiles were plotted as a function of distance with ImageJ software. Scale bar represents 25 μm. (B) The amount of soluble p.Leu104Val KITLG is significantly reduced (p < 10−3, Student’s t test) in the medium of transfected NIH 3T3 cells as measured by ELISA. No soluble KITLG was detected for the p.His67_CysdelinsArg and p.Ser96Ter mutations. Data are means ± SD of four independent experiments. Abbreviation is as follows: WT, wild-type. The American Journal of Human Genetics 2015 97, 647-660DOI: (10.1016/j.ajhg.2015.09.011) Copyright © 2015 The American Society of Human Genetics Terms and Conditions