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De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay  Jessica X.

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Presentation on theme: "De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay  Jessica X."— Presentation transcript:

1 De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay  Jessica X. Chong, Margaret J. McMillin, Kathryn M. Shively, Anita E. Beck, Colby T. Marvin, Jose R. Armenteros, Kati J. Buckingham, Naomi T. Nkinsi, Evan A. Boyle, Margaret N. Berry, Maureen Bocian, Nicola Foulds, Maria Luisa Giovannucci Uzielli, Chad Haldeman- Englert, Raoul C.M. Hennekam, Paige Kaplan, Antonie D. Kline, Catherine L. Mercer, Malgorzata J.M. Nowaczyk, Jolien S. Klein Wassink-Ruiter, Elizabeth W. McPherson, Regina A. Moreno, Angela E. Scheuerle, Vandana Shashi, Cathy A. Stevens, John C. Carey, Arnaud Monteil, Philippe Lory, Holly K. Tabor, Joshua D. Smith, Jay Shendure, Deborah A. Nickerson Michael J. Bamshad, Jay Shendure, Deborah A. Nickerson, Gonçalo R. Abecasis, Peter Anderson, Elizabeth Marchani Blue, Marcus Annable, Brian L. Browning, Kati J. Buckingham, Christina Chen, Jennifer Chin, Jessica X. Chong, Gregory M. Cooper, Colleen P. Davis, Christopher Frazar, Tanya M. Harrell, Zongxiao He, Preti Jain, Gail P. Jarvik, Guillaume Jimenez, Eric Johanson, Goo Jun, Martin Kircher, Tom Kolar, Stephanie A. Krauter, Niklas Krumm, Suzanne M. Leal, Daniel Luksic, Colby T. Marvin, Margaret J. McMillin, Sean McGee, Patrick O’Reilly, Bryan Paeper, Karynne Patterson, Marcos Perez, Sam W. Phillips, Jessica Pijoan, Christa Poel, Frederic Reinier, Peggy D. Robertson, Regie Santos-Cortez, Tristan Shaffer, Cindy Shephard, Kathryn M. Shively, Deborah L. Siegel, Joshua D. Smith, Jeffrey C. Staples, Holly K. Tabor, Monica Tackett, Jason G. Underwood, Marc Wegener, Gao Wang, Marsha M. Wheeler, Qian Yi, Michael J. Bamshad Jessica X. Chong, Margaret J. McMillin, Kathryn M. Shively, Anita E. Beck, Colby T. Marvin, Jose R. Armenteros, Kati J. Buckingham, Naomi T. Nkinsi, Evan A. Boyle, Margaret N. Berry, Maureen Bocian, Nicola Foulds, Maria Luisa Giovannucci Uzielli, Chad Haldeman-Englert, Raoul C.M. Hennekam, Paige Kaplan, Antonie D. Kline, Catherine L. Mercer, Malgorzata J.M. Nowaczyk, Jolien S. Klein Wassink-Ruiter, Elizabeth W. McPherson, Regina A. Moreno, Angela E. Scheuerle, Vandana Shashi, Cathy A. Stevens, John C. Carey, Arnaud Monteil, Philippe Lory, Holly K. Tabor, Joshua D. Smith, Jay Shendure, Deborah A. Nickerson Michael J. Bamshad, Jay Shendure, Deborah A. Nickerson, Gonçalo R. Abecasis, Peter Anderson, Elizabeth Marchani Blue, Marcus Annable, Brian L. Browning, Kati J. Buckingham, Christina Chen, Jennifer Chin, Jessica X. Chong, Gregory M. Cooper, Colleen P. Davis, Christopher Frazar, Tanya M. Harrell, Zongxiao He, Preti Jain, Gail P. Jarvik, Guillaume Jimenez, Eric Johanson, Goo Jun, Martin Kircher, Tom Kolar, Stephanie A. Krauter, Niklas Krumm, Suzanne M. Leal, Daniel Luksic, Colby T. Marvin, Margaret J. McMillin, Sean McGee, Patrick O’Reilly, Bryan Paeper, Karynne Patterson, Marcos Perez, Sam W. Phillips, Jessica Pijoan, Christa Poel, Frederic Reinier, Peggy D. Robertson, Regie Santos-Cortez, Tristan Shaffer, Cindy Shephard, Kathryn M. Shively, Deborah L. Siegel, Joshua D. Smith, Jeffrey C. Staples, Holly K. Tabor, Monica Tackett, Jason G. Underwood, Marc Wegener, Gao Wang, Marsha M. Wheeler, Qian Yi, Michael J. Bamshad  The American Journal of Human Genetics  Volume 96, Issue 3, Pages (March 2015) DOI: /j.ajhg Copyright © 2015 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Phenotypic Characteristics of Each Individual with CLIFAHDD Syndrome Four individuals affected by CLIFAHDD syndrome; all individuals shown have NALCN mutations. Note the short palpebral fissures, flattened nasal root and bridge, large nares, long philtrum, pursed lips, H-shaped dimpling of the chin, and deep nasolabial folds (A, B, C1, D). Camptodactyly of the digits of the hands and ulnar deviation of the wrist (A, B, C, D1, D2) or clubfoot (C3) is present in each affected person. Case identifiers for the individuals shown in this figure correspond to those in Table 1, where there is a detailed description of the phenotype of each affected individual. Figure S1 provides a pedigree of each CLIFAHDD-syndrome-affected family. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Genomic and Protein Structure of NALCN and Spectrum of Mutations that Cause CLIFAHDD Syndrome (A) NALCN is composed of 45 exons, 43 of which are protein coding (blue) and two of which are non-coding (orange). Lines with attached dots indicate the approximate locations of 14 different de novo variants that cause CLIFAHDD syndrome. The color of each dot reflects the nearest transmembrane segment (S1–S6) depicted in (B) and (C). The two mutations between IIIS6 and IVS1 are located in the intracellular loop linking domains III and IV. This loop is known to be involved in the inactivation of voltage-gated sodium channels; however NALCN is not voltage-gated, so the specific function of this loop in NALCN is not known. (B) The predicted protein topology of NALCN is comprised of four homologous pore-forming domains (I–IV), each composed of six transmembrane segments (S1–S6). The bold line represents the polypeptide chain linking segments and domains. The outer ring of P loop amino acid residues (EEKE) that form the ion selectivity filter is represented by filled circles. The approximate positions of variants that cause CLIFAHDD syndrome and infantile hypotonia with psychomotor retardation and characteristic facies are indicated by red-filled circles and black-filled circles, respectively. (C) S1–S3 might have structural functions, whereas four P loops spanning from S5 to S6 form the ion selectivity filter. In other 4x6TM protein superfamily channels, such as SCN1A, the S4 segments initiate opening of the central pore (S5-P loop-S6) in response to voltage changes, however, because NALCN is not voltage-gated, the function of S4 is currently unknown. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Expression of p.Tyr578Ser and p.Leu509Ser NALCN Alterations Prevents Wild-Type NALCN Detection at the Protein Level when Co-Expressed in HEK293T Cells HA-tagged wild-type NALCN channels are not detectable when co-expressed with GFP-tagged NALCN mutant channels in HEK293T cells but are detectable when co-expressed with GFP-tagged wild-type NALCN channels. This experiment is representative of four independent experiments. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

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