Uncovering molecular mechanisms and neuronal pathways involved in SETBP1 disorder using human cell culture models

Haploinsufficiency of the SETBP1 gene causes a neurodevelopmental syndrome
involving expressive speech impairment and mild-moderate developmental delay.
The precise functions of SETBP1, encoding the SET-binding protein 1, are yet to
be discovered. Therefore, the molecular mechanisms or neuronal pathways by
which rare loss-of-function SETBP1 mutations lead to disorder remain largely
unknown. For neurodevelopmental disorders, relevant tissues (brain tissues) and
cell types (neurons) are difficult to obtain. Therefore, patient-derived
induced pluripotent stem cells (iPSCs) that can be differentiated into any cell
lineage provide an important model system. For this purpose, we will use
patient-derived cells including blood lymphocytes and skin fibroblasts to
establish iPSCs. Disease-relevant neuronal models will be established from
these iPSCs in the laboratory for studying the molecular mechanisms and neural
pathways that go awry in SETBP1 disorder.

Our research aims to establish informative tools in the laboratory for studying
the molecular and cellular pathways that are altered in SETBP1 disorder.

This study is a laboratory-based study using cell-culture models derived from
SETBP1 patient fibroblasts and peripheral blood mononuclear cells (PBMCs).
Subjects with SETBP1 disorder and healthy human donors who give written
informed consent will undergo skin biopsy and blood sampling. The collected
tissue samples will be used to generate iPSCs according to standard procedures,
which will be subsequently differentiated into particular neuronal subtypes
e.g. cortical neurons using established protocols. Functional analyses using
transcriptomic/epigenetic approaches and morphological characterisation will be
performed to identify alternations in gene expression, chromatin remodeling and
cellular morphologies between patient- and control-derived iPSC models.

There are no risks associated with participation. The burden for patients will
be small, and the study can only be done using this patient group as SETBP1
disorder is rare. At this stage, virtually nothing is known about the molecular
mechanisms or neuronal pathways by which rare loss-of-function variants of
SETBP1 lead to disorder. Therefore, we aim to establish informative
cell-culture models in the laboratory for studying the fundamental neuronal
mechanisms that go awry in SETBP1 disorder. Results from our study may help
towards future therapeutic development for the disorder.