DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients
| Autor: | Edith Said, Guillem Plasencia, Bryn D. Webb, Laura Castilla-Vallmanya, Daniel Grinberg, Bruce D. Gelb, Ulrich Brinkmann, Klaus Mayer, Roser Urreizti, Susanna Balcells, Neal Cody, Gilad D. Evrony |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Mutation Missense Biology Short stature Article Minor Histocompatibility Antigens Neurodevelopmental disorder Catalytic Domain Genetics medicine Humans Missense mutation Homology modeling DPH1 Sparse hair Child Genetics (clinical) Diphtheria toxin Tumor Suppressor Proteins Malalties neurodegeneratives Infant Correction Proteins Neurodegenerative Diseases Syndrome medicine.disease Pedigree Neurodevelopmental Disorders MCF-7 Cells Female Protein Multimerization medicine.symptom Proteïnes Function (biology) |
| Zdroj: | Eur J Hum Genet |
| Popis: | DPH1 variants have been associated with an ultra-rare and severe neurodevelopmental disorder, mainly characterized by variable developmental delay, short stature, dysmorphic features, and sparse hair. We have identified four new patients (from two different families) carrying novel variants in DPH1, enriching the clinical delineation of the DPH1 syndrome. Using a diphtheria toxin ADP-ribosylation assay, we have analyzed the activity of seven identified variants and demonstrated compromised function for five of them [p.(Leu234Pro); p.(Ala411Argfs*91); p.(Leu164Pro); p.(Leu125Pro); and p.(Tyr112Cys)]. We have built a homology model of the human DPH1-DPH2 heterodimer and have performed molecular dynamics simulations to study the effect of these variants on the catalytic sites as well as on the interactions between subunits of the heterodimer. The results show correlation between loss of activity, reduced size of the opening to the catalytic site, and changes in the size of the catalytic site with clinical severity. This is the first report of functional tests of DPH1 variants associated with the DPH1 syndrome. We demonstrate that the in vitro assay for DPH1 protein activity, together with structural modeling, are useful tools for assessing the effect of the variants on DPH1 function and may be used for predicting patient outcomes and prognoses. |
| Databáze: | OpenAIRE |
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