Mutations Disrupting Selenocysteine Formation Cause Progressive Cerebello-Cerebral Atrophy Orly Agamy, Bruria Ben Zeev, Dorit Lev, Barak Marcus, Dina.

Slides:

Advertisements

Similar presentations

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

Advertisements

Mutations Disrupting Selenocysteine Formation Cause Progressive Cerebello-Cerebral Atrophy Orly Agamy, Bruria Ben Zeev, Dorit Lev, Barak Marcus, Dina Fine,

A Haplotype at STAT2 Introgressed from Neanderthals and Serves as a Candidate of Positive Selection in Papua New Guinea Fernando L. Mendez, Joseph C.

Transmission/Disequilibrium Tests for Extended Marker Haplotypes

A Homozygous Missense Mutation in TGM5 Abolishes Epidermal Transglutaminase 5 Activity and Causes Acral Peeling Skin Syndrome Andrew J. Cassidy, Maurice.

A Second Locus for Familial Generalized Epilepsy with Febrile Seizures Plus Maps to Chromosome 2q21-q33 Stéphanie Baulac, Isabelle Gourfinkel-An, Fabienne.

Familial Deafness, Congenital Heart Defects, and Posterior Embryotoxon Caused by Cysteine Substitution in the First Epidermal-Growth-Factor–Like Domain.

PLA2G6 Mutation Underlies Infantile Neuroaxonal Dystrophy

Genomewide Linkage Scan Identifies a Novel Susceptibility Locus for Restless Legs Syndrome on Chromosome 9p Shenghan Chen, William G. Ondo, Shaoqi Rao,

Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

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

Detection of an Apparent Homozygous 3120G>A Cystic Fibrosis Mutation on a Routine Carrier Screen Denise LaMarche Heaney, Patrick Flume, Lauren Hamilton,

Mutations in DDR2 Gene Cause SMED with Short Limbs and Abnormal Calcifications Ruth Bargal, Valerie Cormier-Daire, Ziva Ben-Neriah, Martine Le Merrer,

Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1 Velina Guergueltcheva, Dimitar N. Azmanov,

Use of Closely Related Affected Individuals for the Genetic Study of Complex Diseases in Founder Populations C. Bourgain, E. Génin, P. Holopainen, K.

Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females Jennifer M. Bain, Megan T. Cho, Aida Telegrafi,

Myotonic Dystrophy Type 2: Human Founder Haplotype and Evolutionary Conservation of the Repeat Tract Christina L. Liquori, Yoshio Ikeda, Marcy Weatherspoon,

Autosomal-Recessive Early-Onset Retinitis Pigmentosa Caused by a Mutation in PDE6G, the Gene Encoding the Gamma Subunit of Rod cGMP Phosphodiesterase

Haplotype-Sharing Analysis Implicates Chromosome 7q36 Harboring DPP6 in Familial Idiopathic Ventricular Fibrillation Marielle Alders, Tamara T. Koopmann,

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

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

A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia John C. van Swieten, Esther Brusse, Bianca M.

Mutations in ABCA12 Underlie the Severe Congenital Skin Disease Harlequin Ichthyosis P. David Kelsell, E. Elizabeth Norgett, Harriet Unsworth, Muy-Teck.

Howard B. Yeon, Noralane M. Lindor, J.G. Seidman, Christine E. Seidman

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

Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4 Jose Bras, Isabel Alonso, Clara Barbot, Maria Manuela Costa, Lee Darwent, Tatiana.

Phosphoserine Aminotransferase Deficiency: A Novel Disorder of the Serine Biosynthesis Pathway Claire E. Hart, Valerie Race, Younes Achouri, Elsa Wiame,

A Locus for Hereditary Sensory Neuropathy with Cough and Gastroesophageal Reflux on Chromosome 3p22-p24 C. Kok, M.L. Kennerson, P.J. Spring, A.J. Ing,

Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ Ortal Barel, Zamir Shorer, Hagit Flusser, Rivka Ofir, Ginat Narkis,

Joubert Syndrome 2 (JBTS2) in Ashkenazi Jews Is Associated with a TMEM216 Mutation Simon Edvardson, Avraham Shaag, Shamir Zenvirt, Yaniv Erlich, Gregory.

Hal M. Hoffman, Fred A. Wright, David H. Broide, Alan A

Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture Yutaka Shimomura, Muhammad.

Koji Suzuki, Tania Bustos, Richard A. Spritz

Mutations in SCARF2 Are Responsible for Van Den Ende-Gupta Syndrome

High Myopia Caused by a Mutation in LEPREL1, Encoding Prolyl 3-Hydroxylase 2 Shikma Mordechai, Libe Gradstein, Annika Pasanen, Rivka Ofir, Khalil El Amour,

A Mutation in the Variable Repeat Region of the Aggrecan Gene (AGC1) Causes a Form of Spondyloepiphyseal Dysplasia Associated with Severe, Premature.

Linkage Analysis Identifies a Novel Locus for Restless Legs Syndrome on Chromosome 2q in a South Tyrolean Population Isolate Irene Pichler, Fabio Marroni,

Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation Asif.

Lethal Contractural Syndrome Type 3 (LCCS3) Is Caused by a Mutation in PIP5K1C, Which Encodes PIPKIγ of the Phophatidylinsitol Pathway Ginat Narkis,

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

John A. Martignetti, Karen E

Retinitis Pigmentosa and Progressive Sensorineural Hearing Loss Caused by a C12258A Mutation in the Mitochondrial MTTS2 Gene Fiona C. Mansergh, Sophia.

Periklis Makrythanasis, Mitsuhiro Kato, Maha S

Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46

Meiotic Microdeletion Breakpoints in the BRCA1 Gene Are Significantly Associated with Symmetric DNA-Sequence Elements Beatrice Schmucker, Michael Krawczak

Hyperchlorhidrosis Caused by Homozygous Mutation in CA12, Encoding Carbonic Anhydrase XII Maya Feldshtein, Suliman Elkrinawi, Baruch Yerushalmi, Barak.

Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46

Gabriella Esposito, Giuseppe Rescigno, Francesco Salvatore

A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev,

A Deleterious Mutation in SAMD9 Causes Normophosphatemic Familial Tumoral Calcinosis Orit Topaz, Margarita Indelman, Ilana Chefetz, Dan Geiger, Aryeh.

Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety of Cancers Nicolas Sévenet, Eammon Sheridan, Daniel Amram, Pascale Schneider,

A Deletion Mutation in COL17A1 in Five Austrian Families with Generalized Atrophic Benign Epidermolysis Bullosa Represents Propagation of an Ancestral.

Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3 Abdul Noor, Christian Windpassinger, Irina Vitcu, Marija.

Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy Daniella.

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

Ataxia-Telangiectasia: Identification and Detection of Founder-Effect Mutations in the ATM Gene in Ethnic Populations Milhan Telatar, Sharon Teraoka,

A Gene for an Autosomal Dominant Scleroatrophic Syndrome Predisposing to Skin Cancer (Huriez Syndrome) Maps to Chromosome 4q23 Young-Ae Lee, Howard P.

Autosomal-Dominant Retinitis Pigmentosa Caused by a Mutation in SNRNP200, a Gene Required for Unwinding of U4/U6 snRNAs Chen Zhao, Deepti L. Bellur,

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

Meconium Ileus Caused by Mutations in GUCY2C, Encoding the CFTR-Activating Guanylate Cyclase 2C Hila Romi, Idan Cohen, Daniella Landau, Suliman Alkrinawi,

Alexandre Irrthum, Marika J

A New Familial Amyotrophic Lateral Sclerosis Locus on Chromosome 16q12

A Homozygous Mutation in ADAMTSL4 Causes Autosomal-Recessive Isolated Ectopia Lentis Dina Ahram, T. Shawn Sato, Abdulghani Kohilan, Marwan Tayeh, Shan.

A Haplotype at STAT2 Introgressed from Neanderthals and Serves as a Candidate of Positive Selection in Papua New Guinea Fernando L. Mendez, Joseph C.

Zuoheng Wang, Mary Sara McPeek The American Journal of Human Genetics

Mutated MESP2 Causes Spondylocostal Dysostosis in Humans

Mutations in Two Nonhomologous Genes in a Head-to-Head Configuration Cause Ellis- van Creveld Syndrome Victor L. Ruiz-Perez, W.J. Stuart Tompson, J. Helen.

A Locus for Autosomal Dominant Hereditary Spastic Ataxia, SAX1,Maps to Chromosome 12p13 I.A. Meijer, C.K. Hand, K.K. Grewal, M.G. Stefanelli, E.J. Ives,

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

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:

Mutations Disrupting Selenocysteine Formation Cause Progressive Cerebello-Cerebral Atrophy Orly Agamy, Bruria Ben Zeev, Dorit Lev, Barak Marcus, Dina Fine, Dan Su, Ginat Narkis, Rivka Ofir, Chen Hoffmann, Esther Leshinsky- Silver, Hagit Flusser, Sara Sivan, Dieter Söll, Tally Lerman-Sagie, Ohad S. Birk The American Journal of Human Genetics Volume 87, Issue 4, Pages 538-544 (October 2010) DOI: 10.1016/j.ajhg.2010.09.007 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Sequential MRI Studies in PCCA Images are of individual 4 of family A (Figure 2). (A) Age 8 months: a T1 coronal image at the level of the occipital lobes demonstrates a normal-looking brain. (B) Age 18 months: a T1 sagital image showing vermian atrophy with mild cerebral atrophy. (C) Age 3 years: a coronal image at the level of the occipital lobes demonstrates severe cerebellar and cerebral atrophy. The American Journal of Human Genetics 2010 87, 538-544DOI: (10.1016/j.ajhg.2010.09.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Genetic Mapping of the Disease-Associated Locus Haplotypes of all four families on chromosome 4p15.2 are shown. The disease-associated haplotype is boxed. Additional microsatellite markers were used for fine mapping the candidate region identified by the genome-wide scan with the 10K SNP arrays. Families A and B are of Iraqi origin. Families C and D are of Iraqi and Moroccan origin. The minimum disease-associated haplotype lies between markers D4S425 and D4S391 for the “Iraqi” haplotype and between markers D4S1551 and rs2048506 for the “Moroccan” haplotype. Gray shading indicates the SepSecS position within the haplotype. The American Journal of Human Genetics 2010 87, 538-544DOI: (10.1016/j.ajhg.2010.09.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 SepSecS Mutations in PCCA Families (A–C) The c.1001A>G SepSecS mutation in exon 8. Sequence analysis is shown for an affected individual (A), a carrier (B), and an unaffected individual (C) in families A and B. (D and E) The c.715G>A mutation in exon 6. Sequence analysis is shown for a carrier (D) and unaffected individuals (E) in families C and D. Affected individuals in families C and D were compound heterozygous for the two mutations. The arrows indicate the positions of the mutations. The American Journal of Human Genetics 2010 87, 538-544DOI: (10.1016/j.ajhg.2010.09.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Alignment of the Mutated Sequence Regions in Some Eukaryotic and Archaeal SepSecS Proteins The American Journal of Human Genetics 2010 87, 538-544DOI: (10.1016/j.ajhg.2010.09.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 5 Functional Studies of the SepSecS Mutations In vivo assays of human SepSecS mutants. Formation of Sec-tRNASec in vivo is assayed by the ability of the wild-type human SepSecS and the mutant variants p.Lys284Thr, p,Ala239Thr, and p.Tyr334Cys to restore the benzyl-viologen-reducing activity of the selenoprotein FDHH in the E. coli ΔselA deletion strain. The Methanocaldococcus jannaschii PSTK is cotransformed to generate the Sep-tRNASec intermediate. K284T is a previously described inactive SepSecS mutant. The American Journal of Human Genetics 2010 87, 538-544DOI: (10.1016/j.ajhg.2010.09.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 6 Structure of Selenocysteine and Its Route of Biosynthesis Seryl-tRNA synthetase attaches serine to tRNASec. (Top) Bacteria use selenocysteine synthase (SelA) to convert Ser-tRNASec directly to Sec-tRNASec. (Bottom) Eukaryotes and archaea employ a two-step conversion; a kinase (PSTK) provides the phosphorylated intermediate Sep-tRNASec, the required substrate of SepSecS (see text). The American Journal of Human Genetics 2010 87, 538-544DOI: (10.1016/j.ajhg.2010.09.007) Copyright © 2010 The American Society of Human Genetics Terms and Conditions