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What is the role of IMPA1 enzyme in Familial Intellectual Disability?

Grant number: 16/09618-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2017
Effective date (End): July 28, 2019
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Mayana Zatz
Grantee:Thalita Cristina Figueiredo Cunha
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):17/19877-0 - Understanding the role of IMPA1 mutation in hippocampal neurons derived from patients with Familial Intellectual Disability, BE.EP.PD


A part of the population in Northeastern Brazil is relatively isolated geographically and has maintained the tradition of consanguineous marriages for generations. These two factors (isolation and inbreeding) increase the risk of birth of people with autosomal recessive diseases, including Intellectual Disabilities (ID), which has an extremely heterogeneous genetic basis and up to 60% of cases of children with ID, the cause is not established. Therefore, these populations are important models to elucidate the genetic causes of different diseases. Thus, in 2012, our research group conducted an epidemiological study to determine the contribution of genetic factors in determining familial intellectual disability in six municipalities from Backlands of Paraiba, previously selected due to high consanguinity rate. Two families with multiple affected individuals with two different forms of severe autosomal recessive ID were selected for clinical and genetic research. From this study, we identified two novel deleterious variants in homozygous associated with ID: a variant (c.418C> T p.Arg140Trp) in the Mediator complex subunit 25 (MED25) and a 5 bp duplication (c.489_483dupGGGCT) in the inositol monophosphatase 1 gene (IMPA1), leading to a frameshift (p.Ser165Trpfs * 10). The IMPA1 gene product is an enzyme responsible for the final step of biotransformation of inositol trisphosphate and diacylglycerol, two important second messengers, important for calcium signaling. Furthermore, IMPA1 is a target for lithium, the main medicament for the treatment of bipolar disorder, thus it is very important from the clinical point of view. However, despite its important physiological functions, no clinical has been assigned to mutation in IMPA1. In order to clearly elucidate the mechanisms by which impairment of IMPA1 can alter important signaling pathways culminating in severe DI, this study will focus on developing neurons derived from Induced Pluripotent Stem Cells (iPSCs) from blood samples of patients with mutation in IMPA1 and unaffected family members (homozygous and heterozygous). In recent years, advances in the development of iPSCs and their differentiation into neuronal cells have been fundamental in the research of neurological diseases. The use of cells derived from iPSCs will allow us to investigate the effects of mutation in IMPA1 gene function in neuronal cell; on disruption of signaling pathway networks and morphofunctional characteristics, allowing future therapeutic approaches. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
WALKER, CHRISTOPHER P.; PESSOA, ANDRE L. S.; FIGUEIREDO, THALITA; RAFFERTY, MEGAN; MELO, UIRA S.; NOBREGA, PAULO R.; MURPHY, NICHOLAS; KOK, FERNANDO; ZATZ, MAYANA; SANTOS, SILVANA; CHO, RAYMOND Y. Loss-of-function mutation in inositol monophosphatase 1 (IMPA1) results in abnormal synchrony in resting-state EEG. ORPHANET JOURNAL OF RARE DISEASES, v. 14, JAN 7 2019. Web of Science Citations: 1.

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