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Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome.
Hum Mutat. 2018 02; 39(2):219-236.HM

Abstract

Heterozygous mutations in the PHOX2B gene are causative of congenital central hypoventilation syndrome (CCHS), a neurocristopathy characterized by defective autonomic control of breathing due to the impaired differentiation of neural crest cells. Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This article provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps ("frame 2" and "frame 3" mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one "frame 3" mutation identified in a patient with isolated CCHS, and one "frame 2" mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCHS.

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Authors+Show Affiliations

Di Lascio S
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
Benfante R
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy. CNR- Neuroscience Institute, Milan, Italy.
Di Zanni E
UOC Genetica Medica, Istituto Giannina Gaslini, Genoa, Italy.
Cardani S
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
Adamo A
UOC Genetica Medica, Istituto Giannina Gaslini, Genoa, Italy.
Fornasari D
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy. CNR- Neuroscience Institute, Milan, Italy.
Ceccherini I
UOC Genetica Medica, Istituto Giannina Gaslini, Genoa, Italy.
Bachetti T
UOC Genetica Medica, Istituto Giannina Gaslini, Genoa, Italy.

MeSH

Electrophoretic Mobility Shift AssayFrameshift MutationHeLa CellsHomeodomain ProteinsHumansHypoventilationMicroscopy, FluorescenceMutationSleep Apnea, CentralTranscription Factors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29098737

Citation

Di Lascio, Simona, et al. "Structural and Functional Differences in PHOX2B Frameshift Mutations Underlie Isolated or Syndromic Congenital Central Hypoventilation Syndrome." Human Mutation, vol. 39, no. 2, 2018, pp. 219-236.
Di Lascio S, Benfante R, Di Zanni E, et al. Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome. Hum Mutat. 2018;39(2):219-236.
Di Lascio, S., Benfante, R., Di Zanni, E., Cardani, S., Adamo, A., Fornasari, D., Ceccherini, I., & Bachetti, T. (2018). Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome. Human Mutation, 39(2), 219-236. https://doi.org/10.1002/humu.23365
Di Lascio S, et al. Structural and Functional Differences in PHOX2B Frameshift Mutations Underlie Isolated or Syndromic Congenital Central Hypoventilation Syndrome. Hum Mutat. 2018;39(2):219-236. PubMed PMID: 29098737.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome. AU - Di Lascio,Simona, AU - Benfante,Roberta, AU - Di Zanni,Eleonora, AU - Cardani,Silvia, AU - Adamo,Annalisa, AU - Fornasari,Diego, AU - Ceccherini,Isabella, AU - Bachetti,Tiziana, Y1 - 2017/11/21/ PY - 2017/07/27/received PY - 2017/10/24/revised PY - 2017/10/29/accepted PY - 2017/11/4/pubmed PY - 2019/1/8/medline PY - 2017/11/4/entrez KW - Hirschsprung's disease KW - PHOX2B KW - congenital central hypoventilation syndrome KW - dominant-negative KW - frameshift mutations KW - gain-of-function KW - loss-of-function KW - neuroblastoma SP - 219 EP - 236 JF - Human mutation JO - Hum Mutat VL - 39 IS - 2 N2 - Heterozygous mutations in the PHOX2B gene are causative of congenital central hypoventilation syndrome (CCHS), a neurocristopathy characterized by defective autonomic control of breathing due to the impaired differentiation of neural crest cells. Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This article provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps ("frame 2" and "frame 3" mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one "frame 3" mutation identified in a patient with isolated CCHS, and one "frame 2" mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCHS. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/29098737/Structural_and_functional_differences_in_PHOX2B_frameshift_mutations_underlie_isolated_or_syndromic_congenital_central_hypoventilation_syndrome_ DB - PRIME DP - Unbound Medicine ER -