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De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features
Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectu...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111011/ https://www.ncbi.nlm.nih.gov/pubmed/27900362 http://dx.doi.org/10.1101/mcs.a001172 |
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author | Webster, Emily Cho, Megan T. Alexander, Nora Desai, Sonal Naidu, Sakkubai Bekheirnia, Mir Reza Lewis, Andrea Retterer, Kyle Juusola, Jane Chung, Wendy K. |
author_facet | Webster, Emily Cho, Megan T. Alexander, Nora Desai, Sonal Naidu, Sakkubai Bekheirnia, Mir Reza Lewis, Andrea Retterer, Kyle Juusola, Jane Chung, Wendy K. |
author_sort | Webster, Emily |
collection | PubMed |
description | Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including PHIP, have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations. PHIP produces multiple protein products, such as PHIP1 (also known as DCAF14), PHIP, and NDRP. PHIP1 is one of the multiple substrate receptors of the proteolytic CUL4-DDB1 ubiquitin ligase complex. CUL4B deficiency has been associated with intellectual disability, central obesity, muscle wasting, and dysmorphic features. The overlapping phenotype associated with CUL4B deficiency suggests that PHIP mutations cause disease through disruption of the ubiquitin ligase pathway. |
format | Online Article Text |
id | pubmed-5111011 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51110112016-11-29 De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features Webster, Emily Cho, Megan T. Alexander, Nora Desai, Sonal Naidu, Sakkubai Bekheirnia, Mir Reza Lewis, Andrea Retterer, Kyle Juusola, Jane Chung, Wendy K. Cold Spring Harb Mol Case Stud Research Report Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including PHIP, have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations. PHIP produces multiple protein products, such as PHIP1 (also known as DCAF14), PHIP, and NDRP. PHIP1 is one of the multiple substrate receptors of the proteolytic CUL4-DDB1 ubiquitin ligase complex. CUL4B deficiency has been associated with intellectual disability, central obesity, muscle wasting, and dysmorphic features. The overlapping phenotype associated with CUL4B deficiency suggests that PHIP mutations cause disease through disruption of the ubiquitin ligase pathway. Cold Spring Harbor Laboratory Press 2016-11 /pmc/articles/PMC5111011/ /pubmed/27900362 http://dx.doi.org/10.1101/mcs.a001172 Text en © 2016 Webster et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted reuse and redistribution provided that the original author and source are credited. |
spellingShingle | Research Report Webster, Emily Cho, Megan T. Alexander, Nora Desai, Sonal Naidu, Sakkubai Bekheirnia, Mir Reza Lewis, Andrea Retterer, Kyle Juusola, Jane Chung, Wendy K. De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features |
title | De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features |
title_full | De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features |
title_fullStr | De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features |
title_full_unstemmed | De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features |
title_short | De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features |
title_sort | de novo phip-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features |
topic | Research Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111011/ https://www.ncbi.nlm.nih.gov/pubmed/27900362 http://dx.doi.org/10.1101/mcs.a001172 |
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