De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Abstract

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

Choanal atresia and stenosis: Development and diseases of the nasal cavity

“…Aniridia 1 patients can exhibit CA in addition to developmental eye defects in association with mutations in PAX6 (Jordan et al, ). Recently, a mutation in SMCHD1 was identified in familial Bosma arhinia microphthalmia syndrome patients, who exhibit CA with severe facial hypoplasia, including agenesis of the nose and eyes (Gordon et al, ; Graham & Lee, ; Shaw et al, ). There are several mechanisms which could explain the development of CA in this set of disorders.…”

“…Biochemical assays have demonstrated enhanced dimerization of FGFRs in human craniosynostoses associated with mutations in FGFRs, which results in exaggerated FGF signaling (Robertson et al, 1998). Also, a number of animal models with mutations equivalent to these human mutations have been established, and they phenocopy human craniosynostosis (Eswarakumar et al, 2006;Gong & The, 2012;Perlyn, Morriss-Kay, Darvann, Tenenbaum, & Ornitz, 2006;Purushothaman, Cox, Maga, & Cunningham, 2011). Interestingly, CA is frequently observed in individuals with craniosynostosis.…”

“…A similar biological mechanism may therefore also underpin Shprintzen-Goldberg syndrome, since this syndrome exhibits craniosynostosis together with CA (Robinson et al, 2005;Saal et al, 1995). Paradoxically, a CA phenotype has not yet been reported in animal models of these FGF signaling-related diseases (Eswarakumar et al, 2006;Gong & The, 2012). The incidence of CA or CS is considerably lower in mice than in humans and this may be due in part to differences in the anatomical structures of the maxillary complex between mice and humans and distinct mechanisms for establishing the airway connection.…”

Smchd1is a maternal effect gene required for autosomal imprinting

“…SMCHD1 function is also relevant in the context of disease (30). Heterozygous mutations in SM-CHD1 are found in two distinct human disorders: loss of function mutations in facioscapulohumeral muscular dystrophy (FSHD) (31), and potentially gain of function mutations in the rare craniofacial disorder Bosma arhinia and microphthalmia (BAMS) (32)(33)(34). The role of SMCHD1 in normal development and disease has led to an increase in interest in how and when it contributes to gene silencing at each of its genomic targets.…”

<b><i>Xenopus</i></b>: An Undervalued Model Organism to Study and Model Human Genetic Disease

“…Patients suffer from an extremely rare syndrome in which the nose is completely absent. Biochemical studies in Xenopus embryos demonstrated that disease mutations resulted in gain-of-function alleles, a finding that would not have been possible by just pursuing loss-of-function approaches [Gordon et al, 2017]. Pediatricians Martina Brueckner and Mustafa Khokha at Yale have systematically identified genes and alleles in children suffering from congenital heart disease (CHD) [Fakhro et al, 2011;Boskovski et al, 2013;Endicott et al, 2015;del Viso et al, 2016;Griffin et al, 2018].…”