ITPR1 Mutation Contributes to Hemifacial Microsomia Spectrum.

Zhixu Liu,Xudong Wang,Jiewen Dai,Hao Sun,Jian Sun,Xiaochen Xue

doi:10.3389/fgene.2021.616329

Abstract

Hemifacial microsomia (HM) is a craniofacial congenital defect involving the first and second branchial arch, mainly characterized by ocular, ear, maxilla-zygoma complex, mandible, and facial nerve malformation. HM follows autosomal dominant inheritance. Whole-exome sequencing of a family revealed a missense mutation in a highly conserved domain of ITPR1. ITPR1 is a calcium ion channel. By studying ITPR1’s expression pattern, we found that ITPR1 participated in craniofacial development, especially the organs that corresponded to the phenotype of HM. In zebrafish, itpr1b, which is homologous to human ITPR1, is closely related to craniofacial bone formation. The knocking down of itpr1b in zebrafish could lead to a remarkable decrease in craniofacial skeleton formation. qRT-PCR suggested that knockdown of itpr1b could increase the expression of plcb4 while decreasing the mRNA level of Dlx5/6. Our findings highlighted ITPR1’s role in craniofacial formation for the first time and suggested that ITPR1 mutation contributes to human HM.

Highlights

Hemifacial microsomia (HM, OMIM:164210) is the second most common craniofacial birth defect after cleft lip and palate
We subsequently performed Sanger sequencing of ITPR1 and RAPGEF2 in all three family members to validate these potentially pathogenic mutations
We reasoned that the ITPR1 mutation was the most probable candidate underlying the HM phenotype in the proband

Summary

INTRODUCTION

Hemifacial microsomia (HM, OMIM:164210) is the second most common craniofacial birth defect after cleft lip and palate. The genetic knowledge of human diseases has been greatly expanded in the past decades, the etiology of HM remains elusive. Both genetic and environmental factors have been suggested as possible causes of HM (Beleza-Meireles et al, 2014). While most HM cases are sporadic, some familial cases have been reported, suggesting genetic mutations as contributing factors for HM. As only 2% of HM patients with family history has been documented, it has been challenging to dissect the genetic causes of HM (Brandstetter and Patel, 2016). Most of the studies considered the autosomal dominant or autosomal recessive inheritance with various chromosomal mutations and genomic imbalances are the causes of HM. We present the genetic studies of a family with autosomal dominant HM and demonstrate the role of the EDN-PLC-DLX5/6 regulatory cascade in HM

MATERIALS AND METHODS

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ETHICS STATEMENT