Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects

Abstract

Laterality defects (LDs) or asymmetrically positioned organs are a group of rare developmental disorders caused by environmental and/or genetic factors. However, the exact molecular pathophysiology of LD is not yet fully characterised. In this context, studying Arab population presents an ideal opportunity to discover the novel molecular basis of diseases owing to the high rate of consanguinity and genetic disorders. Therefore, in the present study, we studied the molecular basis of LD in Arab patients, using next-generation sequencing method. We discovered an extremely rare novel missense variant in MYO1D gene (Pro765Ser) presenting with visceral heterotaxy and left isomerism with polysplenia syndrome. The proband in this index family has inherited this homozygous variant from her heterozygous parents following the autosomal recessive pattern. This is the first report to show MYO1D genetic variant causing left–right axis defects in humans, besides previous known evidence from zebrafish, frog and Drosophila models. Moreover, our multilevel bioinformatics-based structural (protein variant structural modelling, divergence, and stability) analysis has suggested that Ser765 causes minor structural drifts and stability changes, potentially affecting the biophysical and functional properties of MYO1D protein like calmodulin binding and microfilament motor activities. Functional bioinformatics analysis has shown that MYO1D is ubiquitously expressed across several human tissues and is reported to induce severe phenotypes in knockout mouse models. In conclusion, our findings show the expanded genetic spectrum of LD, which could potentially pave way for the novel drug target identification and development of personalised medicine for high-risk families.

Myosin1G promotes Nodal signaling to control Zebrafish Left-Right asymmetry

“…A striking feature of LR asymmetry is that different species use seemingly different mechanisms for the determination of this third body axis 3 . Only recently has the unconventional type I Myosin Myo1D, which was initially identified as a regulator of Drosophila laterality 34,35 , been identified as an evolutionarily conserved regulator of animal LR asymmetry [4][5][6][7] . While studies in fish and frogs uncovered an essential role of Myo1D in LRO morphogenesis [4][5][6] , several observations suggested that additional functions of Myosin1 proteins in LR asymmetry remain still to be uncovered.…”

“…A particularly striking feature of LR asymmetry is the fact that an evolutionary conserved mechanism of symmetry breaking has long remained elusive. Although Nodal proteins of the Transforming Growth Factor  superfamily have long been known to control LR asymmetry in all deuterostome and some protostome species 2,3 , it is only recently that the unconventional type 1 Myosin Myosin1D (Myo1D) has emerged as a potentially universal regulator of animal LR asymmetry [4][5][6][7] . Here, we identify a close orthologue of Myo1D, Myosin1G (Myo1G) as a novel positive regulator of the Nodal signaling pathway.…”

“…In contrast to the central LRO of vertebrate organisms that governs LR asymmetry of all lateralized organs, Drosophila myo1d acts in a local, tissue-autonomous fashion to control genital and visceral laterality 18,35 . Of particular interest, studies in frogs, fish and humans showed that Myo1D is also required for vertebrate LR asymmetry [4][5][6][7] . Zebrafish Myo1D is required for the establishment of a functional symmetry-breaking ciliary LRO flow 5 .…”

Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review

“…The full details of DNA purification, library preparation, sequencing, data filtration, and variation identification strategies we adopted are outlined in our recent publications. 2–4 From the exome data of the proband, we observed a novel, homozygous, and likely pathogenic c.504 C>A variant located in the exon 4 region of the IL2RA gene, resulting in the substitution of a cysteine codon at amino acid position 168 with a termination codon in the IL2RA protein. Sanger sequencing of the proband and of both parents has confirmed the autosomal recessive mode of inheritance of this variant.…”

Movement Asymmetries: from their Molecular Origin to the Analysis of Movement Asymmetries in Sportsmen

“…Thus, this protein can produce de novo changes in shape and orientation not only at a nanometric but also macroscopic scale via chiral interactions with the actin cytoskeleton [67]. A molecular basis of lateral defects was also proven in humans [68]. In fact an extremely rare novel missense variant in MYO1D gene (Pro765Ser) was observed in correlation with visceral heterotaxy and left isomerism in polysplenia syndrome in humans.…”