PLEKHG1: New Potential Candidate Gene for Periventricular White Matter Abnormalities

Abstract

Hypoxic-ischemic brain damage presents a significant neurological challenge, often manifesting during the perinatal period. Specifically, periventricular leukomalacia (PVL) is emerging as a notable contributor to cerebral palsy and intellectual disabilities. It compromises cerebral microcirculation, resulting in insufficient oxygen or blood flow to the periventricular region of the brain. As widely documented, these pathological conditions can be caused by several factors encompassing preterm birth (4-5% of the total cases), as well single cotwin abortion and genetic variants such as those associated with GTPase pathways. Whole exome sequencing (WES) analysis identified a de novo causative variant within the pleckstrin homology domain-containing family G member 1 (PLEKHG1) gene in a patient presenting with PVL. The PLEKHG1 gene is ubiquitously expressed, showing high expression patterns in brain tissues. PLEKHG1 is part of a family of Rho guanine nucleotide exchange factors, and the protein is essential for cell division control protein 42 (CDC42) activation in the GTPase pathway. CDC42 is a key small GTPase of the Rho-subfamily, regulating various cellular functions such as cell morphology, migration, endocytosis, and cell cycle progression. The molecular mechanism involving PLEKHG1 and CDC42 has an intriguing role in the reorientation of cells in the vascular endothelium, thus suggesting that disruption responses to mechanical stress in endothelial cells may be involved in the formation of white matter lesions. Significantly, CDC42 association with white matter abnormalities is underscored by its MIM phenotype number. In contrast, although PLEKHG1 has been recently associated with patients showing white matter hyperintensities, it currently lacks a MIM phenotype number. Additionally, in silico analyses classified the identified variant as pathogenic. Although the patient was born prematurely and subsequently to dichorionic gestation, during which its cotwin died, we suggest that the variant described can strongly contribute to PVL. The aim of the current study is to establish a plausible association between the PLEKHG1 gene and PVL.

Keywords: GTPase pathway; cell division control protein 42 (CDC42); next-generation sequencing; periventricular leukomalacia; white matter hyperintensities; whole exome sequencing.

Figure 1

Detection of the PLEKHG1 gene variant. (a) From upper to bottom: ideogram of the human chromosome 6 with the position of the PLEKHG1 gene in the chromosomal band 6q25.1. Exon/intron organization of the PLEKHG1 gene, and transcriptional direction. Highlight of the nucleotide sequence from the exon 3 shown in (b,c). The position of the first and last nucleotide (nt) here considered are indicated. The red asterisk indicates the observed nucleotide variant. Data from UCSC genome browser, human GRCh/hg38 (https://genome.ucsc.edu, accessed on 3 June 2024). (b) WES results for the examined patient and the healthy parents. Data are presented using the Integrative Genomics Viewer (IGV) visualization tool. (c) Sanger sequencing to highlight the variant c.370A>G identified by WES. The amino acid sequence is shown below the nucleotide sequence. The red asterisk indicates the nucleotide variant. The underlined amino acid is the affected position. The genotype for each subject is shown.

Figure 2

Structure prediction analysis related to the wild-type and mutated PLEKHG1 protein. (a) Wild-type structure prediction of PLEKHG1 protein. (b) Focus on the wild-type Threonine (Thr) residue at position 124. The six hydrogen bonds (2 with Arg251, 2 with Glu120, 1 with Ile121, and 1 with Tyr128) are depicted in light blue. (c) Mutated PLEKHG1 protein structure prediction, which differs from the wild type as result of the diverse number of rearrangements of the hydrogen bonds as a consequence of the genetic variation. (d) Focus on the mutated Alanine residue at position 124. The three hydrogen bonds (Glu120, Thr127 and Tyr128) are depicted in light blue. Figures (a–d) were generated employing UCSF ChimeraX. (e) Graphical representation of the organization of PLEKHG1 functional domains and regions. The Figure was modified from Uniprot database. PhGh: Pleckstrin homology domain-containing family G members 1, 2, and 3 pleckstrin homology (PH) domain.