Neu-Laxova Syndrome Is a Heterogeneous Metabolic Disorder Caused by Defects in Enzymes of the L-Serine Biosynthesis Pathway Rocio Acuna-Hidalgo, Denny.

Slides:

Advertisements

Similar presentations

NEU-LAXOVA SYNDROME IS A HETEROGENEOUS METABOLIC DISORDER CAUSED BY DEFECTS IN ENZYMES OF THE L-SERINE BIOSYNTHESIS PATHWAY ARIANA KARIMINEJAD Kariminejad-Najmabadi.

Advertisements

Germline Missense Mutations Affecting KRAS Isoform B Are Associated with a Severe Noonan Syndrome Phenotype Claudio Carta, Francesca Pantaleoni, Gianfranco.

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

Mutations in FLVCR2 Are Associated with Proliferative Vasculopathy and Hydranencephaly-Hydrocephaly Syndrome (Fowler Syndrome) Esther Meyer, Christopher.

Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A Krista Mahoney, Susan J. Moore, David Buckley, Muhammed Alam, Patrick Parfrey,

Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract Anne E. Hughes, Declan T. Bradley, Malcolm Campbell, Judith Lechner,

Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis- Associated Mutations throughout Adult Life Rocio Acuna-Hidalgo, Hilal Sengul,

Identification of a Novel BBS Gene (BBS12) Highlights the Major Role of a Vertebrate- Specific Branch of Chaperonin-Related Proteins in Bardet-Biedl Syndrome

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

Volume 23, Issue 7, Pages (July 2015)

Thiamine Pyrophosphokinase Deficiency in Encephalopathic Children with Defects in the Pyruvate Oxidation Pathway Johannes A. Mayr, Peter Freisinger,

Functional Consequences of PRODH Missense Mutations

Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function Magnus K. Bjursell,

Crystal Structure of a Human Cleavage Factor CFIm25/CFIm68/RNA Complex Provides an Insight into Poly(A) Site Recognition and RNA Looping Qin Yang, Molly.

Mutations in ZDHHC9, Which Encodes a Palmitoyltransferase of NRAS and HRAS, Cause X-Linked Mental Retardation Associated with a Marfanoid Habitus F.

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

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

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

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

A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome

Exome Sequencing Identifies SLCO2A1 Mutations as a Cause of Primary Hypertrophic Osteoarthropathy Zhenlin Zhang, Weibo Xia, Jinwei He, Zeng Zhang, Yaohua.

Volume 36, Issue 4, Pages (November 2009)

(A) Six missense mutations in six essential genes that are not in annotated functional domains. (A) Six missense mutations in six essential genes that.

Mutations in Contactin-1, a Neural Adhesion and Neuromuscular Junction Protein, Cause a Familial Form of Lethal Congenital Myopathy Alison G. Compton,

Peter Ianakiev, Michael W

Capillary Malformation–Arteriovenous Malformation, a New Clinical and Genetic Disorder Caused by RASA1 Mutations Iiro Eerola, Laurence M. Boon, John.

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

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

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

Crystal Structure of PMM/PGM

De Novo and Inherited Mutations in COL4A2, Encoding the Type IV Collagen α2 Chain Cause Porencephaly Yuriko Yoneda, Kazuhiro Haginoya, Hiroshi Arai,

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

Christian Gilissen, Heleen H

Mutations in the Alpha 1,2-Mannosidase Gene, MAN1B1, Cause Autosomal-Recessive Intellectual Disability Muhammad Arshad Rafiq, Andreas W. Kuss, Lucia.

Cantú Syndrome Is Caused by Mutations in ABCC9

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

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

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

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

Mutations in ZDHHC9, Which Encodes a Palmitoyltransferase of NRAS and HRAS, Cause X-Linked Mental Retardation Associated with a Marfanoid Habitus F.

Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features Emma Tham, Anna Lindstrand, Avni Santani, Helena Malmgren,

PRPS1 Mutations: Four Distinct Syndromes and Potential Treatment

E. coli Dihydroorotate Dehydrogenase Reveals Structural and Functional Distinctions between Different Classes of Dihydroorotate Dehydrogenases Sofie.

Volume 25, Issue 5, Pages e4 (May 2017)

Nadja Ehmke, Almuth Caliebe, Rainer Koenig, Sarina G

Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia Kazutoshi Cho, Masafumi Yamada, Kazunaga.

VPS35 Mutations in Parkinson Disease

Ryan McDaniell, Daniel M. Warthen, Pedro A

Mutations in SPINT2 Cause a Syndromic Form of Congenital Sodium Diarrhea Peter Heinz-Erian, Thomas Müller, Birgit Krabichler, Melanie Schranz, Christian.

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

Crystal Structure of Saccharopine Reductase from Magnaporthe grisea, an Enzyme of the α-Aminoadipate Pathway of Lysine Biosynthesis Eva Johansson, James.

Volume 23, Issue 1, Pages (January 2015)

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes Stefan H. Lelieveld, Laurens Wiel,

X-Linked Dominant Scapuloperoneal Myopathy Is Due to a Mutation in the Gene Encoding Four-and-a-Half-LIM Protein 1 Catarina M. Quinzii, Tuan H. Vu, K.

Volume 70, Issue 6, Pages (September 2006)

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

Human RFT1 Deficiency Leads to a Disorder of N-Linked Glycosylation

Missense Mutation in Pseudouridine Synthase 1 (PUS1) Causes Mitochondrial Myopathy and Sideroblastic Anemia (MLASA) Yelena Bykhovskaya, Kari Casas, Emebet.

Missense Mutations in the N-Terminal Domain of Human Phenylalanine Hydroxylase Interfere with Binding of Regulatory Phenylalanine Torben Gjetting, Marie.

Conversion and Compensatory Evolution of the γ-Crystallin Genes and Identification of a Cataractogenic Mutation That Reverses the Sequence of the Human.

Structural Insights into RIP3-Mediated Necroptotic Signaling

Identification and Functional Consequences of a New Mutation (E155G) in the Gene for GCAP1 That Causes Autosomal Dominant Cone Dystrophy Susan E. Wilkie,

Volume 24, Issue 1, Pages (January 2016)

Gene Mutations in the Succinate Dehydrogenase Subunit SDHB Cause Susceptibility to Familial Pheochromocytoma and to Familial Paraganglioma Dewi Astuti,

Neu-Laxova Syndrome, an Inborn Error of Serine Metabolism, Is Caused by Mutations in PHGDH Ranad Shaheen, Zuhair Rahbeeni, Amal Alhashem, Eissa Faqeih,

Next-Generation Sequencing of a 40 Mb Linkage Interval Reveals TSPAN12 Mutations in Patients with Familial Exudative Vitreoretinopathy Konstantinos Nikopoulos,

A Major Determinant for Binding and Aminoacylation of tRNAAla in Cytoplasmic Alanyl- tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth.

Comparative Genomic Analysis Identifies an ADP-Ribosylation Factor–like Gene as the Cause of Bardet-Biedl Syndrome (BBS3) Annie P. Chiang, Darryl Nishimura,

A Delocalized Proton-Binding Site within a Membrane Protein

Presentation transcript:

Neu-Laxova Syndrome Is a Heterogeneous Metabolic Disorder Caused by Defects in Enzymes of the L-Serine Biosynthesis Pathway Rocio Acuna-Hidalgo, Denny Schanze, Ariana Kariminejad, Ann Nordgren, Mohamad Hasan Kariminejad, Peter Conner, Giedre Grigelioniene, Daniel Nilsson, Magnus Nordenskjöld, Anna Wedell, Christoph Freyer, Anna Wredenberg, Dagmar Wieczorek, Gabriele Gillessen-Kaesbach, Hülya Kayserili, Nursel Elcioglu, Siavash Ghaderi-Sohi, Payman Goodarzi, Hamidreza Setayesh, Maartje van de Vorst, Marloes Steehouwer, Rolph Pfundt, Birgit Krabichler, Cynthia Curry, Malcolm G. MacKenzie, Kym M. Boycott, Christian Gilissen, Andreas R. Janecke, Alexander Hoischen, Martin Zenker The American Journal of Human Genetics Volume 95, Issue 3, Pages 285-293 (September 2014) DOI: 10.1016/j.ajhg.2014.07.012 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Mutations in PHGDH, PSAT1, and PSPH in Individuals with NLS by Homozygosity Mapping and Exome and Sanger Sequencing (A) In one family (family 8), a large homozygous region (68.4–147.0 Mb) on chromosome 1 was identified. This region overlaps the gene PHGDH, in which a mutation has recently been identified to cause NLS. The mutations found in families 7–9 are depicted at the cDNA level (red triangles) with their protein consequences below. PHGDH mutations were identified in a total of three individuals with NLS. These are compared to PHGDH mutations previously identified in individuals with serine-deficiency syndrome (MIM 614023; green triangles)5,6 and NLS (blue triangles).4 (B) Schematic overview of homozygous regions mapped to chromosome 9 in affected individuals from families 1–4. Overlapping homozygous regions (red bars) were identified in four families (family 1 by WES, families 2–4 by microarray analysis); the smallest region of overlap (80.1–82.6 Mb) mapped to chromosome 9. This region contains five protein-coding RefSeq genes (shown in blue), one of which is PSAT1. The mutations found in families 1–6 are depicted at the cDNA level (red triangles) with their protein consequences below. PSAT1 mutations were identified in a total of six individuals with NLS. These are compared to PSAT1 mutations previously identified in an individual with serine-deficiency syndrome (green triangles).7 (C) In one family (family 10), we identified a homozygous PSPH frameshift mutation (56.0–56.1 Mb) located on chromosome 7. The mutations are depicted at the cDNA level (red triangle) with their protein consequences below. A PSPH mutation has been previously reported in a child with serine-deficiency syndrome and Williams-Beuren syndrome (green triangle).8 Triangles outlined in black depict heterozygous mutations, whereas triangles with no outline depict homozygous mutations. The American Journal of Human Genetics 2014 95, 285-293DOI: (10.1016/j.ajhg.2014.07.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Modeling of PHGDH Substitutions (A, C, and D) 3D models of human PHGDH show in red the substitutions p.Arg54Cys (A), p.Glu265Lys (C), and p.Ala286Pro (D). All three substitutions lead to clashes with the side chains of neighboring residues (cyan) in close proximity to the binding site of phosphoglycerate and NAD+ (shown in purple). (B and E) Alignment of PHGDH sequence from multiple organisms shows high conservation of residues Arg54 (B, marked by an asterisk) and Glu265 and Ala286 (E, marked by the left and right asterisks, respectively). Protein sequences for PHGDH orthologs in Homo sapiens (UniProt ID O43175), Mus musculus (UniProt ID Q61753), Xenopus laevis (RefSeq NP_001015929.1), Danio rerio (RefSeq NP_955871.1), Drosophila melanogaster (RefSeq NP_609496.1), Caenorhabditis elegans (RefSeq NP_496868.1), and Mycobacterium tuberculosis (UniProt ID P9WNX3) were obtained from UniProt and Entrez. The 3D structure of wild-type human PHGDH (Protein Data Bank [PDB] ID 2G76) was obtained from the PDB, and substitutions were modeled with the FoldX plugin9 for YASARA. The American Journal of Human Genetics 2014 95, 285-293DOI: (10.1016/j.ajhg.2014.07.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 L-Serine Biosynthesis Pathway De novo biosynthesis of serine is crucial to provide the organism with sufficient levels of this amino acid. The first and limiting step of this pathway is the conversion of 3-phosphoglycerate to 3-phosphohydroxypiruvate by PHGDH (encoded by PHGDH). This is followed by the conversion of 3-phosphohydroxypiruvate to O-phosphoserine by PSAT (encoded by PSAT1). This reaction is accompanied by the transformation of glutamate to α-ketoglutarate and requires the presence of pyridoxal phosphate (PLP). The final step in serine biosynthesis is catalyzed by PSPH (encoded by PSPH), which gives rise to L-serine, the final product of this pathway. The American Journal of Human Genetics 2014 95, 285-293DOI: (10.1016/j.ajhg.2014.07.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 Modeling of PSAT1 Substitutions (A) A 3D model of PSAT from Escherichia coli shows glutamate (molecule in green) localizing closely to the beta sheet where Arg335 (corresponding to human Arg342 and highlighted in purple) is located. (B) Modeling of multiple residue substitutions resulting from frameshift p.Arg342fs6∗, in which the side chain of the wild-type residues (in green) overlaps the side chain of the altered residues (in red). (C) Alignment of PSAT sequence from multiple organisms shows the high conservation of the region surrounding Arg342. The seven altered residues resulting from the frameshift are marked by an asterisk. (D) Alignment of PSAT sequence shows high conservation of Ala99 (marked by an asterisk). (E and F) 3D model of human PSAT substitution p.Ala99Val. Residue Ala99 of PSAT is located in a beta sheet (E, in green). Substitution p.Ala99Val (F, in red) is predicted to disrupt the beta sheet by creating clashes between the large side chains of neighboring residues (shown in cyan). (G) A 3D model of PSAT from E. coli (in white) shows its binding to PLP (molecule in yellow) through the side chain of Lys198 (corresponding to human Lys200, in cyan). When residue Ser177 (corresponding to human Ser179, shown in green) is changed to a leucine (visible in red), the side chain of Lys198 (purple) is displaced and interferes with the binding of PLP. (H) Alignment of PSAT sequences from multiple organisms shows high conservation of residue S179. Protein sequences for PSAT1 orthologs in Homo sapiens (UniProt ID Q9Y617), Mus musculus (UniProt ID Q99K85), Xenopus laevis (RefSeq NP_001016582.1), Danio rerio (RefSeq NP_956113.1), Drosophila melanogaster (UniProt ID Q9VAN0), Caenorhabditis elegans (UniProt ID P91856), and Escherichia coli (UniProt ID Q8XEA7) were obtained from Uniprot and Entrez. 3D models for human PSAT (PDB ID 3E77) and E. coli serC (PDB ID 1BJO11) were obtained from the PDB. The American Journal of Human Genetics 2014 95, 285-293DOI: (10.1016/j.ajhg.2014.07.012) Copyright © 2014 The American Society of Human Genetics Terms and Conditions