Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia
•Two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin were reported.•A novel nonsense HOXA2 mutation was identified, and a mutational hotspot is implicated.•These mutations could impair the activation of HMX1 by interacting with a long-range enhancer. HOX genes are impor...
Gespeichert in:
Veröffentlicht in: | Gene 2020-10, Vol.757, p.144945-144945, Article 144945 |
---|---|
Hauptverfasser: | , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | •Two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin were reported.•A novel nonsense HOXA2 mutation was identified, and a mutational hotspot is implicated.•These mutations could impair the activation of HMX1 by interacting with a long-range enhancer.
HOX genes are important regulatory genes patterning head formation, including development of the ear. Microtia is a congenital ear anomaly characterized by lacking all or part of the structures of the outer ear. To date, only four HOXA2 mutations were reported in families with autosomal-recessive or dominant microtia, with or without hearing impairment. More identified mutations are needed to confirm the correlation between genotype and phenotype. Here, we collect two Chinese families with non-syndromic bilateral microtia. Next generation sequencing identified two heterozygous nonsense HOXA2 mutations, one in each family. One mutation (c.637A > T, p.Lys213*) is newly reported, while the other one (c.703C > T,p.Gln235*) is consistent with a previous report. In mouse, Hoxa2 can bind to a long-range enhancer and regulate expression of the Hmx1 gene, which is a crucial transcription factor in eye and ear development. Using dual luciferase reporter assays, we showed that both HOXA2 mutations have impaired activation of the long-range enhancer of HMX1. In the present study, we report the first two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin and identify a novel mutation. Our results also provide molecular insights about how these nonsense HOXA2 mutations could affect the activation of its downstream target HMX1 by interacting with the long-range enhancer. |
---|---|
ISSN: | 0378-1119 1879-0038 |
DOI: | 10.1016/j.gene.2020.144945 |