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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...

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Autores principales: Webster, Emily, Cho, Megan T., Alexander, Nora, Desai, Sonal, Naidu, Sakkubai, Bekheirnia, Mir Reza, Lewis, Andrea, Retterer, Kyle, Juusola, Jane, Chung, Wendy K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
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.
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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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