Separation of the PROX1 gene from upstream conserved elements in a complex inversion/translocation patient with hypoplastic left heart

Abstract

Hypoplastic left heart (HLH) occurs in at least 1 in 10 000 live births but may be more common in utero. Its causes are poorly understood but a number of affected cases are associated with chromosomal abnormalities. We set out to localize the breakpoints in a patient with sporadic HLH and a de novo translocation. Initial studies showed that the apparently simple 1q41;3q27.1 translocation was actually combined with a 4-Mb inversion, also de novo, of material within 1q41. We therefore localized all four breakpoints and found that no known transcription units were disrupted. However we present a case, based on functional considerations, synteny and position of highly conserved non-coding sequence elements, and the heterozygous Prox1 þ /À mouse phenotype (ventricular hypoplasia), for the involvement of dysregulation of the PROX1 gene in the aetiology of HLH in this case. Accordingly, we show that the spatial expression pattern of PROX1 in the developing human heart is consistent with a role in cardiac development. We suggest that dysregulation of PROX1 gene expression due to separation from its conserved upstream elements is likely to have caused the heart defects observed in this patient, and that PROX1 should be considered as a potential candidate gene for other cases of HLH. The relevance of another breakpoint separating the cardiac gene ESRRG from a conserved downstream element is also discussed.

Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

“…Immunolocalization of proteins in human fetal heart tissue was carried out via protocols previously reported. [33][34][35] Fetal tissue was obtained with informed consent and according to the protocol ethically approved by Southampton and South West Hants LREC. Slides were incubated with primary antibodies (anti-rabbit raised to NR2F2, 1 in 400 [Abcam]; anti-mouse to CD34, 1 in 200 [Novocastra]; Troponin C 1 in 200 [Novocastra]; and SMA, 1 in 100 [Novocastra]).…”

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

“…S4D; Table 1). Some cytoplasmic PROX1 staining was observed, but this is not an unusual occurrence (Duncan et al 2002;Bosco et al 2005;Laerm et al 2007;Gill et al 2009;Yamazaki et al 2009;Dashkevich et al 2010;da Cunha Castro and Galambos 2011;Skog et al 2011). Similarly, VEGFR-3-positive LAM cells were detected in all cases, with greater percentages and more intense immunoreaction in late-stage LAM (mean, 76%; range, 61%-100%) than in early-stage LAM (mean, 50%; range, 40%-75%; p<0.0001) (Fig.…”

Ultradeep Sequencing of a Human Ultraconserved Region Reveals Somatic and Constitutional Genomic Instability

“…Recently, PROX1 has been shown to promote tumour growth and malignant progression in colorectal cancers [34] . Finally, the region between UCR41 and PROX1 can undergo genomic rearrangements that have been associated with heart defects [35] . Altogether, these observations may indeed indicate that UCR41 is under functional constraints in both germline and somatic cells, although the alternative hypothesis of UCR41 as a cold spot for mutations, as proposed for other UCRs [14] , cannot be completely ruled out.…”