Mutations in BMP4 Cause Eye, Brain, and Digit Developmental Anomalies: Overlap between the BMP4 and Hedgehog Signaling Pathways

Abstract

Developmental ocular malformations, including anophthalmia-microphthalmia (AM), are heterogeneous disorders with frequent sporadic or non-Mendelian inheritance. Recurrent interstitial deletions of 14q22-q23 have been associated with AM, sometimes with poly/syndactyly and hypopituitarism. We identify two further cases of AM (one with associated pituitary anomalies) with a 14q22-q23 deletion. Using a positional candidate gene approach, we analyzed the BMP4 (Bone Morphogenetic Protein-4) gene and identified a frameshift mutation (c.226del2, p.S76fs104X) that segregated with AM, retinal dystrophy, myopia, brain anomalies, and polydactyly in a family and a nonconservative missense mutation (c.278A-->G, p.E93G) in a highly conserved base in another family. MR imaging and tractography in the c.226del2 proband revealed a primary brain developmental disorder affecting thalamostriatal and callosal pathways, also present in the affected grandmother. Using in situ hybridization in human embryos, we demonstrate expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits strongly supporting BMP4 as a causative gene for AM, pituitary, and poly/syndactyly. Because BMP4 interacts with HH signaling genes in animals, we evaluated gene expression in human embryos and demonstrate cotemporal and cospatial expression of BMP4 and HH signaling genes. We also identified four cases, some of whom had retinal dystrophy, with "low-penetrant" mutations in both BMP4 and HH signaling genes: SHH (Sonic Hedgehog) or PTCH1 (Patched). We propose that BMP4 is a major gene for AM and/or retinal dystrophy and brain anomalies and may be a candidate gene for myopia and poly/syndactyly. Our finding of low-penetrant variants in BMP4 and HH signaling partners is suggestive of an interaction between the two pathways in humans.

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

“…41 In patients with microphthalmia/coloboma, detection rates for clear-cut pathogenic variants are generally very low, in the vicinity of 1-2% or less as found in our study. 13,42,43 A targeted NGS strategy of the known disease genes could possibly lead to a higher detection rate, as a higher depth of coverage can be achieved with this. However, where such a strategy was undertaken in the severe anophthalmia/microphthalmia group, where there is a known higher detection rate, no disease gene was identified in almost one-third of the patients.…”

“…12 In patients with microphthalmia and anophthalmia, attempts have been made to stratify patients on the basis of the presence of associated eye malformations; however, the overlap in phenotypic features makes this difficult (Figure 1). 13,14 In this study, we applied exome capture and sequencing in patients with developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, and analysed the 56 genes currently known to be implicated in developmental eye disease (Supplementary Table S1). …”

Loss of Otx2 in the Adult Retina Disrupts Retinal Pigment Epithelium Function, Causing Photoreceptor Degeneration

“…Among them, 12 have been implicated in retinal diseases. For instance, germline mutations disrupting the genes encoding the secreted molecule BMP4 and the Retinol Binding Protein receptor/channel STRA6 have been reported to cause severe developmental eye defects leading to microphthalmia or anophthalmia (Bakrania et al, 2008;Casey et al, 2011). Mutations of the 11-cis-retinol dehydrogenase RDH5 gene, a component of the visual cycle, which allows the regeneration of the 11-cis-retinal chromophore, cause retinitis pigmentosa and Fundus albipunctatus diseases in humans (Sato et al, 2004;Sergouniotis et al, 2011;Ajmal et al, 2012).…”

Midbrain-Hindbrain Involvement in Septo-Optic Dysplasia

“…We reviewed the available brain MR midline sagittal images including the posterior cranial fossa of previously reported patients with Otx2 mutations [35][36][37][38] or chromosome 14 deletions including Otx2, [39][40][41][42][43] and we recognized a similar midbrain hypoplasia with a long pons and large superior vermis in 5 patients. 35,36,40,41,43 We therefore suggest that MH abnormalities may have been underestimated in patients with Otx2 mutations or deletion; further studies on larger series are awaited to address this hypothesis. This study has several limitations, mainly including its retrospective design, the relatively small sample size, and the incomplete genetic assessment.…”