2. Academic Validation
  3. DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients

DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients

  • Eur J Hum Genet. 2020 Jan;28(1):64-75. doi: 10.1038/s41431-019-0374-9.
Roser Urreizti # 1,  Klaus Mayer # 2,  Gilad D Evrony # 3,  Edith Said 4 5,  Laura Castilla-Vallmanya 6,  Neal A L Cody 7 8,  Guillem Plasencia 9,  Bruce D Gelb 7 10 11,  Daniel Grinberg 6,  Ulrich Brinkmann # 2,  Bryn D Webb # 7 10 11,  Susanna Balcells # 6
Affiliations

Affiliations

  • 1 Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, CIBERER, Barcelona, Spain. [email protected].
  • 2 Roche Pharma Research and Early Development. Large Molecule Research, Roche Innovation Center, Munich, Nonnenwald 2, 82377, Penzberg, Germany.
  • 3 Center for Human Genetics & Genomics, New York University Langone Health, New York, NY, USA.
  • 4 Section of Medical Genetics, Mater dei Hospital, Msida, Malta.
  • 5 Department of Anatomy and Cell Biology, University of Malta, Msida, Malta.
  • 6 Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, CIBERER, Barcelona, Spain.
  • 7 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8 Sema4, Stamford, CT, USA.
  • 9 Lead Molecular Design, S.L, Sant Cugat del Vallés, Spain.
  • 10 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • # Contributed equally.
PMID: 30877278 DOI: 10.1038/s41431-019-0374-9
Abstract

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.

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