SUMMARY Early in the development of animal embryos, superficial cells of the blastula form a distinct lineage and adopt an epithelial morphology. In different animals, the fate of these primary superficial epithelial (PSE) cells varies, and it is unclear whether pathways governing segregation of blastomeres into the PSE lineage are conserved. Mutations in the gene encoding Interferon Regulatory Factor 6 (IRF6) are associated with syndromic and non-syndromic forms of cleft lip and palate, consistent with a role for Irf6 in development of oral epithelia, and mouse Irf6 targeted null mutant embryos display abnormal differentiation of oral epithelia and skin. In Danio rerio (zebrafish) and Xenopus laevis (African clawed frog) embryos, zygotic irf6 transcripts are present in many epithelial tissues including the presumptive PSE cells and maternal irf6 transcripts are present throughout all cells at the blastula stage. Injection of antisense oligonucleotides with ability to disrupt translation of irf6 transcripts caused little or no effect on development. By contrast, injection of RNA encoding a putative dominant negative Irf6 caused epiboly arrest, loss of gene expression characteristic of the EVL, and rupture of the embryo at late gastrula stage. The dominant negative Irf6 disrupted EVL gene expression in a cell autonomous fashion. These results suggest Irf6 translated in the oocyte or unfertilized egg suffices for early development. Supporting the importance of maternal Irf6, we show that depletion of maternal irf6 transcripts in X. laevis embryos leads to gastrulation defects and rupture of the superficial epithelium. These experiments reveal a conserved role for maternally-encoded Irf6 in differentiation of a simple epithelium in X. laevis and D. rerio. This epithelium constitutes a novel model tissue in which to explore the Irf6 regulatory pathway.

FSHD with a small EcoRI/BlnI fragment is associated with a bilateral, progressive, sloping, high-frequency hearing loss with onset in childhood. Patients with FSHD and small EcoRI/BlnI fragment sizes should have hearing screened, even if the child passed newborn hearing screening.

Introduction: Reported frequencies of cardiomyopathy in limb girdle muscular dystrophy R9 (LGMDR9) vary. We describe the frequency and age at onset of cardiomyopathy in an LDMDR9 cohort. Methods: Echocardiograms from 56 subjects (157 echocardiograms) with LGMDR9 were retrospectively reviewed. The cumulative probability of having an abnormal echocardiogram as a function of age was assessed by survival analysis for interval-censored data by genotype. Correlations between cardiac and clinical function were evaluated. Results: Twenty-five (45%) participants had cardiomyopathy. The median age at first abnormal echocardiogram for subjects homozygous for the c.826C>A variant was 54.2 y compared to 18.1 y for all other fukutin-related protein (FKRP) genotypes (P < .0001). There was a weak correlation between ejection fraction and 10-Meter Walk Test speed (r = 0.25), but no correlation with forced vital capacity (r = 0.08). Discussion: Cardiomyopathy is prevalent among those with LGMDR9 and occurs later in subjects homozygous for the c.826C>A mutation. These data will help to guide surveillance and management.

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