Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

Abstract

Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.Bardet-Biedl ͉ neural crest cells ͉ genetic interaction ͉ zebrafish H irschsprung disease (HSCR, MIM 164761) is the most common (1/5,000 live births) form of structural intestinal obstruction. It is defined by the absence of neural crest (NC)-derived enteric ganglia along a variable length of the bowel, invariably involving the recto-anal junction. This phenotype has been attributed to defects in migration, proliferation, and/or survival of the NC cells (NCC) that normally give rise to all neurons and supporting cells of the enteric nervous system (ENS), defining HSCR as a neurocristopathy. HSCR is also a useful model oligogenic disorder; it displays non-Mendelian modes of inheritance with low, sex-dependant penetrance in isolated HSCR cases. Although oligogenic multiplicative models have been proposed, mutations in the RET proto-oncogene have emerged as pivotal (1-4). Almost all HSCR patients harbor either a heterozygous mutation in the RET coding sequence or, more frequently, a hypomorphic allele in a conserved noncoding element in intron 1 that acts as a spatially restricted transcriptional enhancer (4-6).In addition to HCSR, some 30% of patients also exhibit other congenital anomalies as the result of chromosomal rearrangements [mostly Down syndrome (DS)], monogenic Mendelian disorders regardless of the mode of inheritance, or undiagnosed associations (6). In such cases, penetrance for the HSCR trait is 5 to 70%, suggesting additional predisposing genetic factor(s). Interestingly, alleles at the RET locus can have a role in modifying the risk of HSCR to be associated with several HSCR predisposing syndromes [congenital central hypoventilation, DS, Waardenburg (WS) type IV due to EDNRB mutations, and Bardet-Biedl (BBS)], but not all (Mowat-Wilson and Waardenburg type IV due to SOX10 mutations) (6-8). These observations are suggestive of RET-dependent and RET-independent HSCR cases (9); consistent with RET acting as a modifier gene in some HSCR predisposing syndromes, no correlation between the genotype for the syndrome disease causing gene and the HSCR trait could be drawn in monogenic HSCR syndromes (9,10). Surprisingly, the greatest RET ...

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