Clinical and genetic characterization of individuals with predicted deleterious <i>PHIP</i> variants

Craddock, Kirsten E.; Okur, Volkan; Wilson, Ashley; Gerkes, Erica H.; Ramsey, Keri; Heeley, Jennifer; Juusola, Jane; Vitobello, Antonio; Dupeyron, Marie-Noëlle Bonnet; Faivre, Laurence; Chung, Wendy K.

doi:10.1101/mcs.a004200

Cited by 20 publications

(34 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human DCAF14 functions in mitogenesis ( Farhang-Fallah et al, 2002 ; Podcheko et al, 2007 ), replication origin initiation ( Zhang et al, 2016 ), and regulation of the spindle assembly checkpoint ( Jang et al, 2020 ). DCAF14 is also a prognostic biomarker for metastatic melanoma ( De Semir et al, 2012 ), and deleterious de novo mutations in DCAF14 are associated with developmental abnormalities ( Webster et al, 2016 ; Craddock et al, 2019 ). However, it is not known whether DCAF14 functions in conditions of perturbed replication.…”

Section: Introductionmentioning

confidence: 99%

DCAF14 promotes stalled fork stability to maintain genome integrity

et al. 2021

View full text Add to dashboard Cite

SUMMARY Replication stress response ensures impediments to DNA replication do not compromise replication fork stability and genome integrity. In a process termed replication fork protection, newly synthesized DNA at stalled replication forks is stabilized and protected from nuclease-mediated degradation. We report the identification of DDB1- and CUL4-associated factor 14 (DCAF14), a substrate receptor for Cullin4-RING E3 ligase (CRL4) complex, integral in stabilizing stalled replication forks. DCAF14 localizes rapidly to stalled forks and promotes genome integrity by preventing fork collapse into double-strand breaks (DSBs). Importantly, CRL4 DCAF14 mediates stalled fork protection in a RAD51-dependent manner to protect nascent DNA from MRE11 and DNA2 nucleases. Thus, our study shows replication stress response functions of DCAF14 in genome maintenance.

show abstract

Section: Introductionmentioning

confidence: 99%

DCAF14 promotes stalled fork stability to maintain genome integrity

et al. 2021

View full text Add to dashboard Cite

show abstract

“…T A B L E 1 Clinical characteristics of reported patients with PHIP gene variants, our patient and a 5-year-old female with an identical PHIP gene variant (Webster et al, 2016;Jansen et al, 2018;Craddock et The shortest pathway identified based on experimentally derived evidence connecting PHIP and HEXB was via the SMARCA4 protein, indicating that PHIP binds directly to SMARCA4 (Morgan et al, 2017), which in turn is observed to regulate expression of HEXB mRNA (Hendricks et al, 2004). Hence, the PHIP protein potentially influences the HEXB gene and subsequent protein function.…”

Section: Resultsmentioning

confidence: 96%

“…Dysmorphic features (97%), reduced cognition (94%), and behavioral/psychiatric problems (86%) were the most common or cardinal features of those with PHIP gene variants. Other common features included ophthalmologic problems (72%), obesity/overweight (64%), and chronic fatigue (50%) (Craddock et al, 2019; Jansen et al, 2018). This gene, when disturbed, has led to a clinical condition coined the Chung – Jansen syndrome recognized by the authors reporting on the disturbed gene and characterized by dysmorphic features, cognitive dysfunction, aberrant behavior, and childhood onset of obesity.…”

Section: Discussionmentioning

confidence: 99%

“…To date, PHIP gene variants have been reported in 35 individuals with an assortment of loss‐of‐function and missense variants identified with variable inheritance patterns (Craddock et al, 2019; Jansen et al, 2018; Lee & Zhou, 2007). Most affected individuals have developmental delay with intellectual disability, aberrant behavior, dysmorphic facial features, obesity, and eye problems (Craddock et al, 2019; Lee & Zhou, 2007). All previously reported PHIP gene variants have been unique.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Dietrich

Lovell

Veatch

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Variants in the pleckstrin homology domain‐interacting protein (PHIP) gene are implicated in the clinical phenotype of Chung–Jansen syndrome, which includes dysmorphic features, cognitive dysfunction, aberrant behavior, and childhood onset obesity. Following a systematic literature review, 35 patients are reported to have unique PHIP variants impacting the encoded protein product. We summarize the status and frequency of these variants and relationship to clinical presentation. We also describe an additional patient with a rare, pathogenic variant due to a five base pair deletion leading to an altered codon at I307 but with a stop codon at 22 codons downstream; notably, a variant was identified at the same location as seen previously at protein position I307 in one other subject and a frameshift change at that protein position. We compare the clinical characteristics between the two patients and analyze whether certain types of gene defects impact clinical presentation in previously reported individuals. In addition, we predict structural protein models, which yielded unique differences between the wild‐type and I307P‐related mutant truncated proteins. Protein–protein interactions indicate involvement of POMC and related proteins with potential contribution to obesity, congenital, neuromuscular, and lipid disorders with heart, gastrointestinal, and rheumatoid diseases. With its surrounding proline‐rich region, the I307P point mutation increases susceptibility to conformational rigidity and thermodynamic stability, ultimately impacting function as well as a stop codon downstream. Furthermore, the frameshift mutation seen in our patient may result in a truncated protein with a short abnormal region prior to the stop codon due to a five base pair deletion at I307 or target the protein for nonsense‐mediated mRNA decay.

show abstract

“…Six modules (modules 1, 2, 7, 8, 9, 10) were characterized by enrichment of genes in the embryonic regions, consistent with a role for neurodevelopmental processes mediating susceptibility to obesity ( 93 , 94 ). In fact, these modules contained genes known to participate in brain development, but not functionally characterized with regard to obesity, such as Hmgcr ( 95 ), Klf7 ( 96 ), and Lmo1 ( 97 , 98 ), as well as genes whose role in both development and obesity have been functionally characterized, such as Sim1 ( 78 – 87 ), Creb1 ( 99 , 100 ), Nrp2 ( 14 ), and Phip ( 22 , 23 , 101 , 102 ).…”

Section: Discussionmentioning

confidence: 99%

Gene expression atlas of energy balance brain regions

Rosa¹,

Glover²,

Stratigopoulos³

et al. 2021

JCI Insight

Self Cite

View full text Add to dashboard Cite

Energy balance is controlled by interconnected brain regions in the hypothalamus, brain stem, cortex and limbic system. Gene expression signatures of these regions can help elucidate the pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice and E14.5 C57BL/6NTac embryos punch-biopsies in 16 obesity-relevant brain regions. The expression of 190 known obesity-associated genes (monogenic, rare and low-frequency coding variants, genome-wide association studies (GWAS), syndromic) were analyzed in each anatomical region. Genes associated with these genetic categories of obesity had localized expression patterns across brain regions. Known monogenic obesity causal genes were highly enriched in the arcuate nucleus of the hypothalamus and developing hypothalamus. The obesity-associated genes clustered into distinct 'modules' of similar expression profile and these are distinct from expression 'modules' formed by similar analysis with genes known to be associated with other disease phenotypes (type 1 and type 2 diabetes, autism, breast cancer) in the same energy balance-relevant brain regions.

show abstract

Clinical and genetic characterization of individuals with predicted deleterious PHIP variants

Cited by 20 publications

References 16 publications

DCAF14 promotes stalled fork stability to maintain genome integrity

DCAF14 promotes stalled fork stability to maintain genome integrity

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

Gene expression atlas of energy balance brain regions

Contact Info

Product

Resources

About