Homozygous HOXB1 loss‐of‐function mutation in a large family with hereditary congenital facial paresis

Abstract

Hereditary congenital facial paresis (HCFP) belongs to the congenital cranial dysinnervation disorders. HCFP is characterized by the isolated dysfunction of the seventh cranial nerve and can be associated with hearing loss, strabismus, and orofacial anomalies. Möbius syndrome shares facial palsy with HCFP, but is additionally characterized by limited abduction of the eye(s). Genetic heterogeneity has been documented for HCFP as one locus mapped to chromosome 3q21-q22 (HCFP1) and a second to 10q21.3-q22.1 (HCFP2). The only known causative gene for HCFP is HOXB1 (17q21; HCFP3), encoding a homeodomain-containing transcription factor of the HOX gene family, which are master regulators of early developmental processes. The previously reported HOXB1 mutations change arginine 207 to another residue in the homeodomain and alter binding capacity of HOXB1 for transcriptional co-regulators and DNA. We performed whole exome sequencing in HCFP-affected individuals of a large consanguineous Moroccan family. The homozygous nonsense variant c.66C>G/p.(Tyr22*) in HOXB1 was identified in the four patients with HCFP and ear malformations, while healthy family members carried the mutation in the heterozygous state. This is the first disease-associated HOXB1 mutation with a likely loss-of-function effect suggesting that all HOXB1 variants reported so far also have severe impact on activity of this transcriptional regulator. © 2016 Wiley Periodicals, Inc.

A Novel Loss-of-Function Mutation in HOXB1 Associated with Autosomal Recessive Hereditary Congenital Facial Palsy in a Large Iranian Family

“…2 ) [Webb et al, 2012;Uyguner et al, 2015;Vogel et al, 2016;Sahin et al, 2017]. Our findings consolidate the role of HOXB1 in autosomal recessive HCFP and expand the mutational and phenotypic spectrum of HOXB1 variations in causing CCDD.…”

“…Moreover, there is no clear genotype-phenotype correlation with regards to the type of mutations, their location in the protein, and severity of the pheno- type. However, as seen in Moroccan patients with a lossof-function mutation, 3 of these Iranian patients showed external ear malformations, which were not observed in the other 8 reported patients with missense mutations or in the HOXB1 -deficient mouse model [Webb et al, 2012;Uyguner et al, 2015;Vogel et al, 2016;Sahin et al, 2017]. Further cases of HOXB1-related HCFP would be necessary before we can confidently establish an association between the genotype and the phenotype of external ear malformation in this rare disease.…”

“…Recently, 4 mutations (3 missense and 1 nonsense) in the HOXB1 gene have been identified in 12 patients from 5 unrelated consanguineous families with HCFP3 ( Fig. 1 ) [Webb et al, 2012;Uyguner et al, 2015;Vogel et al, 2016;Sahin et al, 2017]. HOXB1 is a homeobox transcription factor which is part of a developmental regulatory system expressed in the embryological spinal cord and hindbrain and is essential for rhombomere 4 (r4) development [Webb et al, 2012].…”

A novel homozygous HOXB1 mutation in a Turkish family with hereditary congenital facial paresis

“…Similar to the other two reported patients with HCFP, brain MRI in patient II-1 revealed hypoplasia of the facial nerve, and no significant structural anomalies of the vestibulocochlear nerves and abducens nerves [1]. Additionally, clinical features of all affected individuals including hearing loss, midface retrusion, lagophthalmos, oral dysfunction, swallowing difficulties, dysarthria, and speech delay suggested the diagnosis of HCFP.…”

“…In addition, strabismus, hearing loss, feeding difficulties and some recognizable dysmorphic features limited to the orofacial region can be observed [1]. HCFP has genetic heterogeneity and two loci and one gene have been determined so far; chromosome 3q21-q22 (HCFP1; MIM 601471), 10q21.3-q22.1 (HCFP2; MIM 604185) and HOXB1 (17q21; HCFP3; MIM 614744) [2][3][4][5].…”