Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis Andrea Delle.

Slides:

Advertisements

Similar presentations

Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and.

Advertisements

Homozygous Mutations in ADAMTS10 and ADAMTS17 Cause Lenticular Myopia, Ectopia Lentis, Glaucoma, Spherophakia, and Short Stature Jose Morales, Latifa.

GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

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

A Comprehensive Strategy for Accurate Mutation Detection of the Highly Homologous PMS2 Jianli Li, Hongzheng Dai, Yanming Feng, Jia Tang, Stella Chen,

Quantitative Analysis of Survival Motor Neuron Copies: Identification of Subtle SMN1 Mutations in Patients with Spinal Muscular Atrophy, Genotype-Phenotype.

Quantitative Analyses of SMN1 and SMN2 Based on Real-Time LightCycler PCR: Fast and Highly Reliable Carrier Testing and Prediction of Severity of Spinal.

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular.

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

Identification of Small Exonic CNV from Whole-Exome Sequence Data and Application to Autism Spectrum Disorder Christopher S. Poultney, Arthur P. Goldberg,

Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome

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

Kimberly A. Aldinger, Stephen J. Mosca, Martine Tétreault, Jennifer C

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

Exome Sequencing and Functional Analysis Identifies BANF1 Mutation as the Cause of a Hereditary Progeroid Syndrome Xose S. Puente, Victor Quesada, Fernando G.

Keeping Up With the Next Generation

Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy Elena Marrosu, Pierpaolo.

Volume 3, Issue 4, Pages (April 2013)

Shirley Rainier, Jing-Hua Chai, Debra Tokarz, Robert D

Size Polymorphisms in the Human Ultrahigh Sulfur Hair Keratin-Associated Protein 4, KAP4, Gene Family Naoyuki Kariya, Yutaka Shimomura, Masaaki Ito

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

Peter Ianakiev, Michael W

Novel Homozygous and Compound Heterozygous COL17A1 Mutations Associated with Junctional Epidermolysis Bullosa Michaela Floeth, Heike Schäcke, Nadja Hammami-Hauasli,

Structure of the GM2A Gene: Identification of an Exon 2 Nonsense Mutation and a Naturally Occurring Transcript with an In-Frame Deletion of Exon 2 Biao.

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.

Identification of a Novel Mutation R42P in the Gap Junction Protein β-3 Associated with Autosomal Dominant Erythrokeratoderma Variabilis Amanda Wilgoss,

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,

Molecular Therapy - Nucleic Acids

Imprinting at the SMPD1 Locus: Implications for Acid Sphingomyelinase–Deficient Niemann-Pick Disease Calogera M. Simonaro, Jae-Ho Park, Efrat Eliyahu,

Renata C. Gallagher, Birgit Pils, Mohammed Albalwi, Uta Francke

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.

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

Christian Gilissen, Heleen H

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

X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3 Hongwen.

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

Mutation in Exon 1f of PLEC, Leading to Disruption of Plectin Isoform 1f, Causes Autosomal-Recessive Limb-Girdle Muscular Dystrophy Hulya Gundesli, Beril.

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.

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

Brennan Decker, Danielle M. Karyadi, Brian W

Timothy W. Hefferon, Fiona C. Broackes-Carter, Ann Harris, Garry R

Assessing the Functional Characteristics of Synonymous and Nonsynonymous Mutation Candidates by Use of Large DNA Constructs A.M. Eeds, D. Mortlock, R.

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

Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene Silke Appenzeller, Anja Schirmacher, Hartmut Halfter,

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

The Gene Mutated in Variant Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN6) and in nclf Mutant Mice Encodes a Novel Predicted Transmembrane Protein

Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites Melissa Lee, Patrick Roos, Neeraj Sharma,

De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay Valerie A.

Adaptor Protein Complex 4 Deficiency Causes Severe Autosomal-Recessive Intellectual Disability, Progressive Spastic Paraplegia, Shy Character, and Short.

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

Mutations in the Gene Encoding Capillary Morphogenesis Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis Sandra Hanks,

Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene Ralf Giess,

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

Mutations in HPSE2 Cause Urofacial Syndrome

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

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

Two Exon-Skipping Mutations as the Molecular Basis of Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria) Ken L. Chambliss, Debra.

Intragenic telSMN Mutations: Frequency, Distribution, Evidence of a Founder Effect, and Modification of the Spinal Muscular Atrophy Phenotype by cenSMN.

Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease Ming Li, Ruhong Cheng, Jianying Liang, Heng Yan,

Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome Amy E. Merrill, Barry Merriman, Claire.

Quantitative Analysis of Survival Motor Neuron Copies: Identification of Subtle SMN1 Mutations in Patients with Spinal Muscular Atrophy, Genotype-Phenotype.

Epigenetic Allele Silencing Unveils Recessive RYR1 Mutations in Core Myopathies Haiyan Zhou, Martin Brockington, Heinz Jungbluth, David Monk, Philip Stanier,

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular.

Exon Skipping in IVD RNA Processing in Isovaleric Acidemia Caused by Point Mutations in the Coding Region of the IVD Gene Jerry Vockley, Peter K. Rogan,

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

BMPER Mutation in Diaphanospondylodysostosis Identified by Ancestral Autozygosity Mapping and Targeted High-Throughput Sequencing Vincent A. Funari,

Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive

Presentation transcript:

Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis Andrea Delle Vedove, Markus Storbeck, Raoul Heller, Irmgard Hölker, Malavika Hebbar, Anju Shukla, Olafur Magnusson, Sebahattin Cirak, Katta M. Girisha, Mary O’Driscoll, Bart Loeys, Brunhilde Wirth The American Journal of Human Genetics Volume 99, Issue 5, Pages 1206-1216 (November 2016) DOI: 10.1016/j.ajhg.2016.09.019 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Homozygous Frameshift Variants in PIEZO2 in Ten Affected Individuals of Four Independent Families (A–D) Pedigrees and Sanger sequencing results of four independent families with homozygous frameshift mutations (A–C) or homozygous exon deletions (D) in PIEZO2. DNA was not available for individuals with gray outline. The unequivocal individual identifier is assembled of family, generation, and individual (e.g., A-III.1). Deletion of a genomic region comprising the PIEZO2 exons 6 and 7 in individual D-II.2 (D) was confirmed by PCR analysis and by identification of the breakpoint region. PIEZO2 exons 5, 6, 7, and 8 were amplified in multiplex with RYR1 exon 93 as PCR-positive control. Breakpoint regions were identified by Sanger sequencing of a long-range PCR product amplified from the genomic region between exon 5 and exon 8. (E) PIEZO2 protein structure and mutations identified: homozygous loss-of-function mutations (black) and dominant gain-of-function mutations for DA3 (blue), DA5 (green), and MWKS (red) are given. Protein isoforms refer to UniProt entry Q9H5I5. Bright regions indicate putative transmembrane domains (approximated scale); blue regions indicate missing or inserted regions in different isoforms. The bottom line shows exons in which homozygous frameshift mutations were identified. The American Journal of Human Genetics 2016 99, 1206-1216DOI: (10.1016/j.ajhg.2016.09.019) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Phenotypic Characteristics of Affected Individuals with Homozygous LoF Variants in PIEZO2 Photographs of individuals with homozygous frameshift variants/exon deletions in PIEZO2. (A) Frontal photographs. Facial muscle weakness was present in some of the examined affected individuals. Note weak facial expression/hypomimia in individual B-III.4 and C-II.2. (B) Foot deformities were present in all examined affected individuals including congenital bilateral talipes equinovarus, pes planus, sandal gap deformity, and other valgus and varus deformities. (C) Common hand abnormalities included arachnodactyly and camptodactyly. Note the characteristic hyperextension of the proximal interphalangeal joint with flexion of the metacarpophalangeal joint of the thumb (duck bill deformity) that was present in the majority of case subjects. (D) Spinal skeletal deformities were present in all affected individuals and have been in part surgically corrected. Affected individuals have a short stature (e.g., A-III.5). The American Journal of Human Genetics 2016 99, 1206-1216DOI: (10.1016/j.ajhg.2016.09.019) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 Homozygous Frameshift Variants in PIEZO2 Cause Nonsense-Mediated Decay of PIEZO2 Transcripts Determination of PIEZO2 transcript levels by semiquantitative PCR. RNA was isolated from control and affected individual-derived fibroblasts that were either treated or non-treated with an NMD-inhibiting agent. 300 ng of RNA was reversely transcribed into cDNA. (A) RT-PCR of SRSF6 and PIEZO2. SRSF6 (PCR product size: 253 bp) is a physiological target of NMD used as control. A region spanning exons 51 and 52 of PIEZO2 (28 cycles; PCR product size: 306 bp) was amplified. Both cycloheximide (C) and emetine (E) treatment efficiently inhibited NMD. HPRT1 was amplified as loading control (product size: 168 bp). (B) Quantification of PIEZO2 transcripts. Bars show the mean and standard errors of triplicate NMD inhibition experiments. Asterisks indicate statistical significance (p < 0.05). (C) Oligonucleotides in PIEZO2 exons 12 and 14 were used to coordinately amplify transcripts containing (FL) or lacking (Δ13) exon 13 (38 cycles; FL-PCR product size: 430 bp; Δ13-PCR product size: 199 bp). (D) Δ13 PCR products were Sanger sequenced demonstrating skipping of PIEZO2 exon 13 in presence of the variant c.1550_1552delGCTinsCGAA. Abbreviations are as follows: C, cycloheximide; E, emetine; hom, homozygous; het, heterozygous; FL, full-length; Δ13, delta exon 13 (exon skipping). The American Journal of Human Genetics 2016 99, 1206-1216DOI: (10.1016/j.ajhg.2016.09.019) Copyright © 2016 American Society of Human Genetics Terms and Conditions