Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes

Abstract

Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. By studying multiplex families, we mapped this disorder to chromosome 2q23.3-31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets.

Figure 1

Schematic representation of LRP2 mutations and corresponding megalin domains. LRP2 sequencing uncovered missense, nonsense, frameshift or splice junction mutations in individuals with DBS/FOAR from seven kindreds. Mutations are indicated adjacent to the megalin extracellular domains that they affect; mutation ‘hotspots’ or genotype-phenotype correlations are not apparent. Mat, maternally inherited mutation; pat, paternally inherited mutation (Supplementary Table 3).

Figure 2

MRI abnormalities in individuals with DBS/FOAR. (a) Sagittal T1-weighted magnetic resonance image of subject 1, kindred 5, showing ACC with associated absence of cingulate gyrus. (b) Sagittal T1-weighted magnetic resonance image of subject IV-6, kindred 1, showing arrested development of corpus callosum with truncation of posterior body, absence of splenium and rostrum of corpus callosum, partially empty sella (s) and small-appearing pons (P). (c,d) Axial FSE T2-weighted magnetic resonance image of subject IV-6, kindred 1, showing subependymal nodular heterotopia (c) and enlarged globes with small colobomas at the optic nerve heads (d). (e) Axial computed tomography of temporal bones of subject IV-6, kindred 1, showing globular malformation of the left horizontal semicircular canal and vestibule. Abnormalities are indicated by arrows in a–e. (f–i) Brain cortical surface reconstruction from spoiled gradient-echo (SPGR) structural magnetic resonance image. f shows a frontal right view and g shows a top view for a 4-year-old control. Central sulcus, precentral gyrus and postcentral gyrus are labeled by a red curve, a white arrow and a yellow arrow, respectively. h shows a frontal right view and i shows a top view for subject IV-6, kindred 1, with DBS/FOAR. Note abnormally developed frontal lobe and unrecognizable abnormally placed central sulcus.