Is Arg5 in HOXDNA binding domain of HOXB1 hot spot for congenital facial paralysis mimicking Moebius syndrome?

Abstract

Congenital facial paralysis (CFP) and Moebius syndrome (MBS; MIM157900) are highly sporadic, formulating classical gene identi����ication algorithmsdif����icult, assigning candidate gene approach compatible. Mutantmice for Hoxb1 were long before reported to present features of facial nervedefects, resembling MBS, only very recently associated with human phenotype.Currently, homozygous c.619C>T in HOXB1 revealed in the two CFPaffected individuals from two different families, both from the same geographicorigin, altering arginine to cysteine at 207 (p.arg207cys) correspondsarg5 residue of the HOXB1 homeodomain.We have screened our cohort of 33 sporadic MBS and CFP patients for mutationon HOXB1 and identi����ied homozygous c.620G>A in one consanguineousfamily. Alteration changes the same neutral-polar arginine, via second nucleotide,resulting to basic-polar histidine (p.arg207his). Clinical investigationof our case presented left esotropia, right ����lattened/broad nasal bridge,external ear defects, high arched palate, bilateral cranial nerve VII dysfunction,diagnosed as CFP. We further screened HOXB1 in 56 DNA samples ofMBS cases, referred to us from Radbound University Nijmegen-Holland,none found to carry any pathological alteration. It is surprising that, such arare disorder with three only identi����ied mutation striking the same conservedamino acid, delegating arg5 the achilles of HOXB1 protein. Up to date,out of 267 families with MBS or with the facial weakness, component ofMBS (177 from Webb et al.2012, 56 from Nijmegan group and 34 from ourcenter), only three reported to carry mutations in HOXB1 gene, ����iguring theprevalence of HOXB1 mutation frequency to be 1.12%.