ITPR1 Mutation Contributes to Hemifacial Microsomia Spectrum

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.

The etiology, clinical features, and treatment options of hemifacial microsomia

“…The etiology of HFM remains unclear. HFM is primarily sporadic, but 2%–10% of patients had a family history of inheritance and exhibited either an autosomal dominant or recessive inheritance pattern (Ballesta‐Martínez et al, 2013; Liu et al, 2021; Ou et al, 2008; Vinay et al, 2009). In a genome‐wide search for linkage between two significant genetic HFM families, Kelberman et al (2001) discovered that a region on chromosome 14q32 measuring about 10.7 cM was highly suggestive of being the pathogenic locus for HFM.…”

“…In a genome‐wide search for linkage between two significant genetic HFM families, Kelberman et al (2001) discovered that a region on chromosome 14q32 measuring about 10.7 cM was highly suggestive of being the pathogenic locus for HFM. This discovery is extremely important, and many studies have since examined the pathogenic genes of HFM‐positive families, including OTX2 (Ballesta‐Martínez et al, 2013), EYA1 (Bragagnolo et al, 2018), GATA3 (Bragagnolo et al, 2018), MYT1 (Lopez et al, 2016), ITPR1 (Liu et al, 2021), and SF3B2 (Timberlake et al, 2021). However, sporadic occurrences have not been associated with mutations of these potential gene loci.…”

Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome

“…The etiology of OAVS is still largely unknown and felt to be multifactorial due to both environmental (maternal diabetes, antenatal exposure to vasoactive medications, smoking and twinning) and genetic factors during early embryogenesis [4]. With the widespread adoption of exome or genome sequencing, several genes have now been associated with OAVS [6][7][8][9][10][11], although many have only been identified through segregation in multi-generational single families. Most recently, a large exome/ genome sequencing effort of trios identified haploinsufficient variants in SF3B2 in multiple families segregating OAVS [12].…”

Exploration of Novel Genetic Evidence and Clinical Significance Into Hemifacial Microsomia Pathogenesis

“…A WES result of missense mutation in ITPR1 also revealed its genotype-phenotype correlation to HFM by Itpr1 expression in mouse embryo craniofacial regions, increased transcription of itpr1 in zebrafish craniofacial bone calcification and severe head skeleton dysmorphology consequent to transient itpr1 knockdown 7…”

“…6 A WES result of missense mutation in ITPR1 also revealed its genotype-phenotype correlation to HFM by Itpr1 expression in mouse embryo craniofacial regions, increased transcription of itpr1 in zebrafish craniofacial bone calcification and severe head skeleton dysmorphology consequent to transient itpr1 knockdown. 7 MYT1, a gene known to regulate retinoic acid signaling and central nervous development, 8,9 has been established further causality to HFM spectrum by recurrent clinical reports on unrelated patients with mutations in this gene, 10 and on a deleterious single nucleotide variant and an enrichment of copy number variation (CNV) on its neighboring topologically associating domain. 11 A sporadically reported nonsense variant in ZYG11B was also found causative with regulating role in cell proliferation and retinoic acid pathway, and its homolog zyg11b in zebrafish with crucial role in head cartilage formation.…”