Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia Elizabeth J. Bhoj,

Slides:

Advertisements

Similar presentations

Previous Estimates of Mitochondrial DNA Mutation Level Variance Did Not Account for Sampling Error: Comparing the mtDNA Genetic Bottleneck in Mice and.

Advertisements

Connexin Mutations in Skin Disease and Hearing Loss David P. Kelsell, Wei-Li Di, Mark J. Houseman The American Journal of Human Genetics Volume 68, Issue.

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

Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome Sarah B. Pierce,

Fragile X and X-Linked Intellectual Disability: Four Decades of Discovery Herbert A. Lubs, Roger E. Stevenson, Charles E. Schwartz The American Journal.

TCTN3 Mutations Cause Mohr-Majewski Syndrome

The Primordial Growth Disorder 3-M Syndrome Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1 Dan Hanson, Philip G. Murray, Amit Sud, Samia A.

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

A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex Jing You, Nara L. Sobreira,

Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin Peter.

Exome Sequencing in Brown-Vialetto-Van Laere Syndrome

PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

TCTN3 Mutations Cause Mohr-Majewski Syndrome

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

Jennifer J. Johnston, Monica Y. Sanchez-Contreras, Kim M

XYLT1 Mutations in Desbuquois Dysplasia Type 2

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

The American Journal of Human Genetics

Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy Jessica X. Chong,

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

De Novo Mutations in MLL Cause Wiedemann-Steiner Syndrome

Mutations of POLR3A Encoding a Catalytic Subunit of RNA Polymerase Pol III Cause a Recessive Hypomyelinating Leukodystrophy Geneviève Bernard, Eliane.

Mutations in TCF4, Encoding a Class I Basic Helix-Loop-Helix Transcription Factor, Are Responsible for Pitt-Hopkins Syndrome, a Severe Epileptic Encephalopathy.

Mutations in ASPH Cause Facial Dysmorphism, Lens Dislocation, Anterior-Segment Abnormalities, and Spontaneous Filtering Blebs, or Traboulsi Syndrome

Mutations in LRPAP1 Are Associated with Severe Myopia in Humans

Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation Marc Trimborn, Sandra M. Bell, Clive Felix, Yasmin Rashid, Hussain Jafri,

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy Marisa I. Mendes, Mariana.

Noah C. Jenkins, Jae Jung, Tong Liu, Megan Wilde, Sheri L

Figure 2 Facial appearance and brain imaging

Mutations in CSPP1 Lead to Classical Joubert Syndrome

Manitoba Aboriginal Kindred with Original Cerebro-Oculo-Facio-Skeletal Syndrome Has a Mutation in the Cockayne Syndrome Group B (CSB) Gene Lisiane B.

Simon Edvardson, Claudia M. Nicolae, Pankaj B

The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria Jennifer J. Johnston, Andrea L. Gropman,

Fatema Zahrani, Mohammed A. Aldahmesh, Muneera J. Alshammari, Selwa A

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

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

Cowden Syndrome–Affected Patients with PTEN Promoter Mutations Demonstrate Abnormal Protein Translation Rosemary E. Teresi, Kevin M. Zbuk, Marcus G.

Christina A. Gurnett, Farhang Alaee, Lisa M. Kruse, David M

Exome Sequencing Identifies Autosomal-Dominant SRP72 Mutations Associated with Familial Aplasia and Myelodysplasia Michael Kirwan, Amanda J. Walne, Vincent.

Erratum The American Journal of Human Genetics

Mutations in DVL1 Cause an Osteosclerotic Form of Robinow Syndrome

Antisense basic fibroblast growth factor alters the time course of mitogen-activated protein kinase in arterialized vein graft remodeling Akimasa Yamashita,

De Novo Mutations of the Gene Encoding the Histone Acetyltransferase KAT6B Cause Genitopatellar Syndrome Michael A. Simpson, Charu Deshpande, Dimitra.

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella Shuyan Tang, Xiong Wang,

Periklis Makrythanasis, Mitsuhiro Kato, Maha S

Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes

Ryan McDaniell, Daniel M. Warthen, Pedro A

The Primordial Growth Disorder 3-M Syndrome Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1 Dan Hanson, Philip G. Murray, Amit Sud, Samia A.

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

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

Interpretation of Association Signals and Identification of Causal Variants from Genome- wide Association Studies Kai Wang, Samuel P. Dickson, Catherine.

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

Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans Ranad Shaheen, Hanan E. Shamseldin, Catrina M.

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

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

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

Recessive Mutations in DOCK6, Encoding the Guanidine Nucleotide Exchange Factor DOCK6, Lead to Abnormal Actin Cytoskeleton Organization and Adams-Oliver.

Mutations in CHEK2 Associated with Prostate Cancer Risk

Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain

PGAP2 Mutations, Affecting the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Syndrome Peter M. Krawitz, Yoshiko Murakami,

Identification and Characterization of a Mutation, in the Human UDP-Galactose-4- Epimerase Gene, Associated with Generalized Epimerase-Deficiency Galactosemia

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

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

Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L

Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome Carine Le Goff, Curtis Rogers, Wilfried.

Niemann-Pick Disease Type C: Spectrum of HE1 Mutations and Genotype/Phenotype Correlations in the NPC2 Group Gilles Millat, Karim Chikh, Saule Naureckiene,

Risk Prediction of Complex Diseases from Family History and Known Susceptibility Loci, with Applications for Cancer Screening Hon-Cheong So, Johnny S.H.

Mutations in the Fatty Acid 2-Hydroxylase Gene Are Associated with Leukodystrophy with Spastic Paraparesis and Dystonia Simon Edvardson, Hiroko Hama,

Mutated MESP2 Causes Spondylocostal Dysostosis in Humans

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

Presentation transcript:

Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia Elizabeth J. Bhoj, Dong Li, Margaret Harr, Shimon Edvardson, Orly Elpeleg, Elizabeth Chisholm, Jane Juusola, Ganka Douglas, Maria J. Guillen Sacoto, Karine Siquier-Pernet, Abdelkrim Saadi, Christine Bole-Feysot, Patrick Nitschke, Alekhya Narravula, Maria Walke, Michele B. Horner, Debra-Lynn Day-Salvatore, Parul Jayakar, Samantha A. Schrier Vergano, Mark A. Tarnopolsky, Madhuri Hegde, Laurence Colleaux, Peter Crino, Hakon Hakonarson The American Journal of Human Genetics Volume 98, Issue 4, Pages 782-788 (April 2016) DOI: 10.1016/j.ajhg.2016.03.016 Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 1 Diagram of TBCK with Reported Variants and Facial Features and Brain Imaging of Affected Individuals (A) A diagram of TBCK includes known domains and the variants present in the individuals described in this report. Abbreviations are as follows: Hom, homozygous; and Comp Het, compound heterozygous. (B–D and G–I) Facial features of individuals 8-1 (B) and 2-1 (G), affected siblings 4-1 (C) and 4-2 (H), and affected siblings 6-1 (D) and 6-2 (I). Individuals 8-1 and 2-1 have coarse features with significant macroglossia, and individuals 4-1 and 4-2 have no significant facial dysmorphisms. Note the mild dysmorphic features, including a wide forehead, bulbous nose, open mouth with macroglossia, thick lips, deep palate, and prognathic mandible, in individual 6-1 and the wide forehead and short neck in individual 6-2. (E, F, and I–K) Brain MRI of individuals 6-1 (E), 6-2 (J), and 7-1 (F and K) demonstrates discrete abnormalities of the periventricular and parietal white matter in both studies. The American Journal of Human Genetics 2016 98, 782-788DOI: (10.1016/j.ajhg.2016.03.016) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 2 Western Blot Demonstrates Absent TBCK and Decreased mTOR Signaling in Lympoblastic Cells of Affected Individuals Western blots of immortalized lymphocytes (LCLs) from a control individual and individuals 1-1 and 1-2; both affected individuals have homozygous frameshift variants. (A) Top: TBCK levels were lower in proband LCLs (from individual 1-1 and 1-2) than in control LCLs. Middle: levels of mTOR and non-phosphorylated S6 were unchanged, but levels of PS6 isoform Ser235/236 were lower in LCLs with mutant TBCK than in control cells. Bottom: GAPDH was used as a loading control. (B) Relative densitometry graph shows the levels of PS6 isoform Ser235/236 in fibroblasts with mutant TBCK (from individuals 1-1 and 1-2) and control fibroblasts across independent western blots in triplicate. Lines depict the SE. Cells were provided by Fowzan S. Alkuraya and colleagues of the King Faisal Specialist Hospital and Research Center. The American Journal of Human Genetics 2016 98, 782-788DOI: (10.1016/j.ajhg.2016.03.016) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 3 Western Blots Demonstrate Decreased mTOR Signaling in Fibroblasts of Affected Individuals Levels of PS6 isoforms Ser235/236 (A) and Ser240/244 (B) were lower in fibroblasts harboring mutant TBCK (from individual 2-1) than in control cells. The blot demonstrates that levels of PS6 isoform Ser235/236 were, on average, 36% (range 31%–41%, SEM ± 5) lower in fibroblasts with mutant TBCK than in control fibroblasts (p < 0.05). There was no change in the level of non-phosphorylated S6 or mTOR in either LCLs or fibroblasts containing TBCK mutations. GAPDH was used as a loading control. The American Journal of Human Genetics 2016 98, 782-788DOI: (10.1016/j.ajhg.2016.03.016) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 4 Western Blot Demonstrates that Leucine Normalizes mTOR Signaling in Fibroblasts of Affected Individuals Enhanced mTOR signaling in TBCK mutant fibroblasts (individual 2-1) with the addition of exogenous L-leucine (600 μg/ml). The western blot demonstrates increased levels of PS6 (24 ± 4%; p < 0.05). GAPDH was used as a loading control. The American Journal of Human Genetics 2016 98, 782-788DOI: (10.1016/j.ajhg.2016.03.016) Copyright © 2016 The American Society of Human Genetics Terms and Conditions