Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome Lekbir Baala, Sophie Audollent, Jéléna Martinovic, Catherine Ozilou, Marie-Claude.

Slides:

Advertisements

Similar presentations

Antenatal Presentation of Bardet-Biedl Syndrome May Mimic Meckel Syndrome Houda Karmous-Benailly, Jelena Martinovic, Marie-Claire Gubler, Yoann Sirot,

Advertisements

TCTN3 Mutations Cause Mohr-Majewski Syndrome

Figure 1 Phenotype and genotype of an undiagnosed family with autosomal recessive spastic ataxia Phenotype and genotype of an undiagnosed family with autosomal.

Identification of a Major Susceptibility Locus for Restless Legs Syndrome on Chromosome 12q Alex Desautels, Gustavo Turecki, Jacques Montplaisir, Adolfo.

Homozygous Defects in LMNA, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy in Human (Charcot-Marie-Tooth Disorder.

Homozygosity Mapping in Families with Joubert Syndrome Identifies a Locus on Chromosome 9q34.3 and Evidence for Genetic Heterogeneity Kathrin Saar, Lihadh.

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.

Robustness and Power of the Maximum-Likelihood–Binomial and Maximum-Likelihood– Score Methods, in Multipoint Linkage Analysis of Affected-Sibship Data

Use of Homozygosity Mapping to Identify a Region on Chromosome 1 Bearing a Defective Gene That Causes Autosomal Recessive Homozygous Hypercholesterolemia.

Neurological Phenotype in Waardenburg Syndrome Type 4 Correlates with Novel SOX10 Truncating Mutations and Expression in Developing Brain Renaud L. Touraine,

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

Fine Localization of the Nijmegen Breakage Syndrome Gene to 8q21: Evidence for a Common Founder Haplotype Karen M. Cerosaletti, Ethan Lange, Heather.

Genomewide Scan in German Families Reveals Evidence for a Novel Psoriasis- Susceptibility Locus on Chromosome 19p13 Young-Ae Lee, Franz Rüschendorf, Christine.

Soraya Beiraghi, Swapan K. Nath, Matthew Gaines, Desh D

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

Using Genomic Inbreeding Coefficient Estimates for Homozygosity Mapping of Rare Recessive Traits: Application to Taybi-Linder Syndrome Anne-Louise Leutenegger,

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

Volume 58, Issue 2, Pages (August 2000)

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.

TCTN3 Mutations Cause Mohr-Majewski Syndrome

Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease

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

Volume 77, Issue 4, Pages (February 2010)

Tamara Rogers, David Chandler, Dora Angelicheva, P. K

A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

The American Journal of Human Genetics

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,

Recurrent Williams-Beuren Syndrome in a Sibship Suggestive of Maternal Germ-Line Mosaicism Ali Kara-Mostefa, Odile Raoul, Stanislas Lyonnet, Jeanne Amiel,

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

Ehlers-Danlos Syndrome with Severe Early-Onset Periodontal Disease (EDS-VIII) Is a Distinct, Heterogeneous Disorder with One Predisposition Gene at Chromosome.

CRB2 Mutations Produce a Phenotype Resembling Congenital Nephrosis, Finnish Type, with Cerebral Ventriculomegaly and Raised Alpha-Fetoprotein Anne Slavotinek,

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

Evidence for a Nonallelic Heterogeneity of Epidermodysplasia Verruciformis with Two Susceptibility Loci Mapped to Chromosome Regions 2p21–p24 and 17q25

Joubert Syndrome in French Canadians and Identification of Mutations in CEP104 Myriam Srour, Fadi F. Hamdan, Dianalee McKnight, Erica Davis, Hanna Mandel,

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

Familial Juvenile Hyperuricemic Nephropathy: Localization of the Gene on Chromosome 16p11.2—and Evidence for Genetic Heterogeneity Blanka Stibůrková,

Combined Analysis of Genome Scans of Dutch and Finnish Families Reveals a Susceptibility Locus for High-Density Lipoprotein Cholesterol on Chromosome.

DPY19L2 Deletion as a Major Cause of Globozoospermia

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,

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

Genetic studies into inherited and sporadic hemolytic uremic syndrome

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

Homozygosity and Linkage-Disequilibrium Mapping of the Syndrome of Congenital Hypoparathyroidism, Growth and Mental Retardation, and Dysmorphism to a.

Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15 Sonja Hillebrandt, Claudia Goos, Siegfried.

Evidence That the Penetrance of Mutations at the RP11 Locus Causing Dominant Retinitis Pigmentosa Is Influenced by a Gene Linked to the Homologous RP11.

Antenatal Presentation of Bardet-Biedl Syndrome May Mimic Meckel Syndrome Houda Karmous-Benailly, Jelena Martinovic, Marie-Claire Gubler, Yoann Sirot,

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

Mapping of Gene Loci for Nephronophthisis Type 4 and Senior-Løken Syndrome, to Chromosome 1p36 Maria J. Schuermann, Edgar Otto, Achim Becker, Katrin.

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

Mutations in Fibroblast Growth-Factor Receptor 3 in Sporadic Cases of Achondroplasia Occur Exclusively on the Paternally Derived Chromosome Douglas J.

Identification, by Homozygosity Mapping, of a Novel Locus for Autosomal Recessive Congenital Ichthyosis on Chromosome 17p, and Evidence for Further Genetic.

Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy Puzzle Jonna Tallila, Eveliina Jakkula, Leena Peltonen,

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

Whole-Genome Scan, in a Complex Disease, Using 11,245 Single-Nucleotide Polymorphisms: Comparison with Microsatellites Sally John, Neil Shephard, Guoying.

Identification of a New Gene Locus for Adolescent Nephronophthisis, on Chromosome 3q22 in a Large Venezuelan Pedigree Heymut Omran, Carmen Fernandez,

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

The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome

A New Familial Amyotrophic Lateral Sclerosis Locus on Chromosome 16q12

C. Denier, S. Goutagny, P. Labauge, V. Krivosic, M Arnoult, A

Assignment of the Muscle-Eye-Brain Disease Gene to 1p32-p34 by Linkage Analysis and Homozygosity Mapping Bru Cormand, Kristiina Avela, Helena Pihko,

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

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.

Homozygosity Mapping in Families with Joubert Syndrome Identifies a Locus on Chromosome 9q34.3 and Evidence for Genetic Heterogeneity Kathrin Saar, Lihadh.

Mutations of NPHP2 and NPHP3 in infantile nephronophthisis

Gonçalo R. Abecasis, Janis E. Wigginton

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

Genome-wide High-Density SNP-Based Linkage Analysis of Infantile Hypertrophic Pyloric Stenosis Identifies Loci on Chromosomes 11q14-q22 and Xq23 Kate.

Linkage of Familial Hemophagocytic Lymphohistiocytosis to 10q21-22 and Evidence for Heterogeneity Rémi Dufourcq-Lagelouse, Nada Jabado, Françoise Le.

Presentation transcript:

Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome Lekbir Baala, Sophie Audollent, Jéléna Martinovic, Catherine Ozilou, Marie-Claude Babron, Sivanthiny Sivanandamoorthy, Sophie Saunier, Rémi Salomon, Marie Gonzales, Eleanor Rattenberry, Chantal Esculpavit, Annick Toutain, Claude Moraine, Philippe Parent, Pascale Marcorelles, Marie-Christine Dauge, Joëlle Roume, Martine Le Merrer, Vardiella Meiner, Karen Meir, Françoise Menez, Anne- Marie Beaufrère, Christine Francannet, Julia Tantau, Martine Sinico, Yves Dumez, Fiona MacDonald, Arnold Munnich, Stanislas Lyonnet, Marie-Claire Gubler, Emmanuelle Génin, Colin A. Johnson, Michel Vekemans, Férechté Encha-Razavi, Tania Attié-Bitach The American Journal of Human Genetics Volume 81, Issue 1, Pages 170-179 (July 2007) DOI: 10.1086/519494 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1. Genomewide scan. a, Results of the multipoint linkage analysis with microsatellite markers performed in eight families (Fam), with use of MERLIN software6 under the assumption of a fully penetrant recessive model with a disease-allele of frequency of 0.0001 and with allowance for heterogeneity between families. The highest HLOD score (2.45) was found at marker D12S326. b, Summary of HLOD observed at chromosome 12 in each of the eight families. Six of the eight families show a LOD score at marker D12S326, D12S351, or D12S346 close to its maximal value (LODmax). c, Haplotyping at the 12q21 locus in the six families showing potential linkage to chromosome 12. Homozygosity for two consecutive markers—D12S326 and D12S351 (boxed)—is observed in five affected siblings of four families (1, 2, 11, and 12). In family 1, the first child and case 6 (gray) are affected with ARPKD. The American Journal of Human Genetics 2007 81, 170-179DOI: (10.1086/519494) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2. Haplotype analysis of families 3 and 4. a, Haplotyping analysis with Affymetrix 10K SNP chips of affected siblings 335 and 336 of family 3, which identified a single homozygous region on chromosome 127 between markers rs1882186 and rs1389064. This 10-Mb region includes CEP290. b, Analysis of four microsatellite markers flanking CEP290 in family 3, which confirmed homozygosity in only affected siblings 335 and 336 and reduced the telomeric boundary of the interval to position 88.71 (D12S1678). In family 4 carrying the same maternally inherited p.Asp128GlufsX34 mutation as family 3, the maternal disease haplotype is different from fetuses 335 and 336 and does not suggest a founder effect for the mutation. Positions of SNP and microsatellite markers are given according to the UCSC Genome Browser database. The American Journal of Human Genetics 2007 81, 170-179DOI: (10.1086/519494) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. Sequence chromatographs of CEP290 mutations identified in the present study. Mutation numbering is based on cDNA sequence, where +1 corresponds to the A of the ATG translation codon in the GenBank cDNA reference sequence NM_025114.3. The predicted effect of the mutation on the protein is also given with the amino acid number. The American Journal of Human Genetics 2007 81, 170-179DOI: (10.1086/519494) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4. Pathological features of fetal cases with CEP290 mutations. Histological sections (HES staining) of kidney (left), liver (middle), and brain stem/cerebellum (right) of MKS- and MKS-like–affected fetuses with CEP290 mutations. In families 1–4 (a–d) and 10 (m), kidney histology shows major abnormalities characteristic of MKS: cysts in both kidney and medulla, growing from periphery to center. Small areas of conserved nephrogenesis are observed in the subcapsular zone. In family 9 (l), kidney histology shows conserved corticomedullary organization with several generations of mature glomeruli. Microcysts are found in the deep cortex, but tubular microcysts are observed mainly in medulla (black arrows). Liver histology shows a portal fibrosis with persistent ductal plate (arrows) and/or BDP/dilatation (arrowheads). Subject 4 (b) had the most-severe liver fibroadenomatosis, whereas the liver anomalies were moderate and focal in families 9 (n) and 10 (o). Brain-stem/cerebellum transverse sections are shown for five cases. i, Subject 4: section of the mesencephalon showing the chaotic organization of fibers and tracts (arrows) and atretic aqueduct of Sylvius. j, Subject 3501: section at the level of the pons showing severely dilated V4, enlarged cerebellar peduncle (P), chaotic organization of fibers and tracts (arrows), hypoplastic vermis (arrowhead), and cerebellar hemispheres (ce). k, Fetus 304. Note the inverted MTS with dysmorphic V4 flanked with enlarged and elongated cerebellar peduncles (P). For fetuses 381 (p) and 03/485 (q), the section at the level of the pons shows an inverted MTS with chaotic fibers and tracts (arrows), dysmorphic V4, severe hypoplasia of vermis (arrowhead), and well-developed cerebellar hemispheres. Fam=family. The American Journal of Human Genetics 2007 81, 170-179DOI: (10.1086/519494) Copyright © 2007 The American Society of Human Genetics Terms and Conditions