A novel de novo mutation in MYT1, the unique OAVS gene identified so far

Abstract

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.

Figure 1

Pedigree and photographs of the patient carrying the c.323C>T (p.Ser108Leu) variant in MYT1. (a) Family tree and electrophoregram showing the de novo heterozygous missense variant. (b) Photographs of the proband showing facial asymmetry, right anotia and left microtia at age 1 and 17 years (top and bottom panels, respectively). (c) X-rays of proband at 1 year showing hypoplasia the right mandibular branch (arrow).

Figure 2

MYT1 variants altered regulation of RARs genes and CYP26A1. RT-qPCR analysis of RARA (a), RARB(b), RARG(c) and CYP26A1 (d) are shown following overexpression of either empty, MYT1-WT, MYT1-p.Ser105Leu or MYT1-p.Ser108Leu pCS2+ expression vector. The relative transcript level was calculated as fold change using the 2^−ΔΔCt method (n=3–6). Statistical significance was evaluated using t-test (*P<0.05; **P<0.01; ***P<0.001).