Patient ROC presented a very large de novo ~5Mb deletion encompassing the ABCB4 locus and 20 additional genes including ABCB1 gene (Supplementary Table 1). Surprisingly, this patient presented a less severe phenotype only consisting in CIC, while being haploinsufficient for 21 genes. Unlike the ABCB4 more info gene, none of these 20 genes is known to be associated with an inherited human disease according to the OMIM database (http://www.ncbi.nlm.nih.gov/omim). Variable expressions of the liver diseases caused by ABCB4 mutations have previously been reported. Comorbidity factors, environmental influences, or unknown genetic modifiers may modulate these phenotypes.13, 19 Our observations reinforce the potential existence of these genetic modifiers.

Gene dosage technologies have allowed the identification of ABCB4 deletions in a significant subset (7%) of patient with LPAC syndrome. An early diagnosis of this biliary disease would be beneficial because of the potential preventive effect of UDCA on the biliary complications. These data must now be taken into account in patient diagnosis and follow-up. Acknowledgments We thank the patients for their participation. We thank all the clinicians from France, who provided the samples for this study. Notes The authors declare no conflict of interest. Footnotes Supplementary Information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg) Supplementary Material Supplementary Figure 1 Click here for additional data file.(536K, tif) Supplementary Figure Legend Click here for additional data file.

(22K, doc) Supplementary Table 1 Click here for additional data file.(64K, doc)
The corpus luteum (CL) is a transient endocrine organ that forms in the ovary of mammals after ovulation. If pregnancy does not occur, the CL regresses, allowing a new cycle to begin [1]. Luteal regression induced by endometrial prostaglandin F2�� (PGF) is characterized by a reduction in progesterone (P4) production (functional luteolysis) and by tissue degeneration via apoptosis (structural luteolysis) [2, 3]. The major event that causes the structural regression of the CL is luteal cell death [4]. P4 is indispensable for the establishment and maintenance of pregnancy and is also known to suppress apoptosis in bovine luteal cells [5].

Since luteinizing hormone (LH) stimulates P4 production via a variety of signaling molecules in bovine luteal cells, such as cyclic AMP (cAMP), lipoxygenase and phospholipid-specific phospholipase-C [6,7,8], LH may play luteoprotective roles in the bovine CL during the active luteal phase. PGs regulate CL function in many species. Although the uterine prostanoid PGF induces luteolysis in cattle [3], it neither reduces P4 secretion nor induces apoptosis in cultured bovine luteal cells [9,10,11]. Furthermore, PGF stimulates P4 production as well as PGE2 by cultured Drug_discovery luteal cells [9, 10].