This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

Analysis of cis-regulatory elements is central to understanding the genomic program for development. The scl/tal-1 transcription factor is essential for lineage commitment to blood cell formation and previous studies identified an scl enhancer (the ؉18/19 element) which was sufficient to target the vast majority of hematopoietic stem cells, together with hematopoietic progenitors and endothelium. Moreover, expression of scl under control of the ؉18/19 enhancer rescued blood progenitor formation in scl ؊/؊ embryos. However, here we demonstrate by using a knockout approach that, within the endogenous scl locus, the ؉18/19 enhancer is not necessary for the initiation of scl transcription or for the formation of hematopoietic cells. These results led to the identification of a bifunctional 5 enhancer (؊3.8 element), which targets expression to hematopoietic progenitors and endothelium, contains conserved critical Ets sites, and is bound by Ets family transcription factors, including Fli-1 and Elf-1. These data demonstrate that two geographically distinct but functionally related enhancers regulate scl transcription in hematopoietic progenitors and endothelial cells and suggest that enhancers with dual hematopoietic-endothelial activity may represent a general strategy for regulating blood and endothelial development.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau () gene. Since this discovery, additional mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other exons. In this study, we show that the mutations induced a dysregulation of splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new alterations and reveals a novel complex splicing regulation of the gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.