<scp><i>PHIP</i></scp> gene variants with protein modeling, interactions, and clinical phenotypes

Dietrich, Jordan; Lovell, Scott; Veatch, Olivia J.; Butler, Merlin G.

doi:10.1002/ajmg.a.62557

Cited by 5 publications

(3 citation statements)

References 31 publications

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“…Aoi et al investigated a cohort of patients with suspected Cornelia-de-Lange syndrome (CdLS, OMIM #122470) and identified one individual with a missense substitution in PHIP ( Aoi et al, 2019 ), while Kaur et al extended the phenotypic spectrum with a case of CHUJANS also showing hypothyroidism and small kidneys ( Kaur and Panigrahi, 2021 ). The latest publication reviewed 35 already reported individuals with PHIP variants together with one newly identified individual and sheds light on the impact of the variants on the structure of the protein by means of protein modeling ( Dietrich et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals

Kampmeier

Leitão

Parenti

et al. 2023

Front. Cell Dev. Biol.

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In 2016 and 2018, Chung, Jansen and others described a new syndrome caused by haploinsufficiency of PHIP (pleckstrin homology domain interacting protein, OMIM *612,870) and mainly characterized by developmental delay (DD), learning difficulties/intellectual disability (ID), behavioral abnormalities, facial dysmorphism and obesity (CHUJANS, OMIM #617991). So far, PHIP alterations appear to be a rare cause of DD/ID. “Omics” technologies such as exome sequencing or array analyses have led to the identification of distinct types of alterations of PHIP, including, truncating variants, missense substitutions, splice variants and large deletions encompassing portions of the gene or the entire gene as well as adjacent genomic regions. We collected clinical and genetic data of 23 individuals with PHIP-associated Chung-Jansen syndrome (CHUJANS) from all over Europe. Follow-up investigations (e.g. Sanger sequencing, qPCR or Fluorescence-in-situ-Hybridization) and segregation analysis showed either de novo occurrence or inheritance from an also (mildly) affected parent. In accordance with previously described patients, almost all individuals reported here show developmental delay (22/23), learning disability or ID (22/23), behavioral abnormalities (20/23), weight problems (13/23) and characteristic craniofacial features (i.e. large ears/earlobes, prominent eyebrows, anteverted nares and long philtrum (23/23)). To further investigate the facial gestalt of individuals with CHUJANS, we performed facial analysis using the GestaltMatcher approach. By this, we could establish that PHIP patients are indistinguishable based on the type of PHIP alteration (e.g. missense, loss-of-function, splice site) but show a significant difference to the average face of healthy individuals as well as to individuals with Prader-Willi syndrome (PWS, OMIM #176270) or with a CUL4B-alteration (Intellectual developmental disorder, X-linked, syndromic, Cabezas type, OMIM #300354). Our findings expand the mutational and clinical spectrum of CHUJANS. We discuss the molecular and clinical features in comparison to the published individuals. The fact that some variants were inherited from a mildly affected parent further illustrates the variability of the associated phenotype and outlines the importance of a thorough clinical evaluation combined with genetic analyses for accurate diagnosis and counselling.

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Section: Introductionmentioning

confidence: 99%

PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals

Kampmeier

Leitão

Parenti

et al. 2023

Front. Cell Dev. Biol.

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“…However, PHIP ’s chromatin binding is disrupted in neurodevelopmental disorders [ 64 ]. Loss-of-function mutations in the PHIP gene are associated with the neurodevelopmental disorder Chung–Jansen syndrome [ 65 ], which includes dysmorphic features, cognitive dysfunction, aberrant behavior, childhood-onset obesity, and severe childhood obesity related to the inhibition of pro-opiomelanocortin (POMC) expression: a neuropeptide that suppresses appetite [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

The Relevance of Reperfusion Stroke Therapy for miR-9-3p and miR-9-5p Expression in Acute Stroke—A Preliminary Study

Gendosz de Carrillo,

Kocikowska,

Rak

et al. 2024

IJMS

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Reperfusion stroke therapy is a modern treatment that involves thrombolysis and the mechanical removal of thrombus from the extracranial and/or cerebral arteries, thereby increasing penumbra reperfusion. After reperfusion therapy, 46% of patients are able to live independently 3 months after stroke onset. MicroRNAs (miRNAs) are essential regulators in the development of cerebral ischemia/reperfusion injury and the efficacy of the applied treatment. The first aim of this study was to examine the change in serum miRNA levels via next-generation sequencing (NGS) 10 days after the onset of acute stroke and reperfusion treatment. Next, the predictive values of the bioinformatics analysis of miRNA gene targets for the assessment of brain ischemic response to reperfusion treatment were explored. Human serum samples were collected from patients on days 1 and 10 after stroke onset and reperfusion treatment. The samples were subjected to NGS and then validated using qRT-PCR. Differentially expressed miRNAs (DEmiRNAs) were used for enrichment analysis. Hsa-miR-9-3p and hsa-miR-9-5p expression were downregulated on day 10 compared to reperfusion treatment on day 1 after stroke. The functional analysis of miRNA target genes revealed a strong association between the identified miRNA and stroke-related biological processes related to neuroregeneration signaling pathways. Hsa-miR-9-3p and hsa-miR-9-5p are potential candidates for the further exploration of reperfusion treatment efficacy in stroke patients.

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“…Hence, genetic factors can be divided into the following three categories: Mendelian (monogenic) syndromic obesity, Mendelian non-syndromic obesity, and polygenic obesity. Meanwhile, NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings [ 5 , 11 ]. The results of these recent investigations need to be replicated to warrant further consideration.…”

Section: Introductionmentioning

confidence: 99%

Genetics of Obesity in Humans: A Clinical Review

Mahmoud

Kimonis

Butler

2022

IJMS

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Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader–Willi, fragile X, Bardet–Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), the melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and the neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings.

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PHIP gene variants with protein modeling, interactions, and clinical phenotypes

Cited by 5 publications

References 31 publications

PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals

PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals

The Relevance of Reperfusion Stroke Therapy for miR-9-3p and miR-9-5p Expression in Acute Stroke—A Preliminary Study

Genetics of Obesity in Humans: A Clinical Review

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