Understanding the Molecular Basis of Miller-Dieker Syndrome

Abstract

Miller-Dieker Syndrome (MDS) is a rare neurodevelopmental disorder caused by a heterozygous deletion of approximately 26 genes within the MDS locus of human chromosome 17. MDS, which affects 1 in 100,000 babies, can lead to a range of phenotypes, including lissencephaly, severe neurological defects, distinctive facial abnormalities, cognitive impairments, seizures, growth retardation, and congenital heart and liver abnormalities. One hallmark feature of MDS is an unusually smooth brain surface due to abnormal neuronal migration during early brain development. Several genes located within the MDS locus have been implicated in the pathogenesis of MDS, including PAFAH1B1, YWHAE, CRK, and METTL16. These genes play a role in the molecular and cellular pathways that are vital for neuronal migration, the proper development of the cerebral cortex, and protein translation in MDS. Improved model systems, such as MDS patient-derived organoids and multi-omics analyses indicate that WNT/β-catenin signaling, calcium signaling, S-adenosyl methionine (SAM) homeostasis, mammalian target of rapamycin (mTOR) signaling, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and others are dysfunctional in MDS. This review of MDS integrates details at the clinical level alongside newly emerging details at the molecular and cellular levels, which may inform the development of novel therapeutic strategies for MDS.

Keywords: MDS; gene expression; lissencephaly; rare disease; therapeutics.

Figure 1

Schematic illustration of MDS-related genes on chromosome 17. Names of all protein-coding (black) and select non-coding (gray) genes in the MDS locus and neighboring regions of human chromosome 17p13.3 are shown. Gene order was obtained from the Human Genome Project Ensemble Database and UCSC Genome Browser [53,54]. Please note that 50 “ENSG” non-coding RNAs were omitted for brevity. Deletions specific to each human-derived MDS cell line (GM09208, GM06097, and GM26025) and reported samples from MDS patients (arbitrarily labeled as MDS 1–3) are denoted by lines with gene names at the boundaries. Base pairs with a question mark denote the uncertainty of the exact deletion. The dotted lines denote additional sequence not shown for spatial reasons. The 1-Mbp region from the telomeric end to the MDS locus (i.e., genes spanning from SCGB1C2 to TRARG1) in 17p13.3 is not shown. Schematic is not drawn to scale. Figure was created using BioRender [55].

Figure 2

Graphical summary of MDS phenotypes and their associated molecular pathways and genes. Common manifestations of MDS phenotypes are clustered as nervous system defects [4,18,60,61,62,63,64,65], facial dysmorphic features [20,23,24,25,27,37,62,64,66,67], physical and other manifestations [35,38,49,62,64], cardiac abnormalities [39,61,62], liver defects [62], gastrointestinal defects [62,68], and kidney defects [39,62]. Gene names associated with each specific phenotype based on clinical studies are listed in parentheses, and the related molecular pathways, indicated with an arrow from an appropriate bullet point, are on the left or right side. Curly brackets indicate molecular pathways applying to all the covered bullet points. Parenthetical gene names at the bottom of purple box apply to all bullet points. Genes that are encoded in the MDS locus (see Figure 1) are in blue font, while genes in gray are predicted to be associated with each phenotype based on pathway analyses using differentially expressed genes determined by a multi-omics study [61]. Figure was created using BioRender [55].

Figure 3

Key gene actions in MDS progression and their role in brain development. Summary of the key genes discovered in MDS progression (PAFAH1B1/LIS1, YWHAE/14-3-3ε, NDEL, CRK, METTL16, WNT), participating in processes such as neuronal migration, microtubule organization, actin cytoskeleton stabilization, and protein translation [18,61,63,89]. Figure was created using BioRender [55].

Figure 4

Potential therapeutic targets for treating MDS symptoms. The schematic summarizes the key metabolic pathways, and their associated effectors implicated in MDS. The pathways are shown with key enzymes, receptors (RTK, TRKA, cytokine receptor, FZD6), molecules involved, and their potential effects on cellular processes. Areas where drug intervention (magenta color) could inhibit (red blunt end) or enhance (green arrow) the metabolic activity to improve treatment outcomes are indicated. Figure was created using BioRender [55].