title: 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(+/-) 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.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, UK.
authors.forename: Harinder K
authors.initials: HK
authors.lastname: Gill
authors.forename: Sian R
authors.initials: SR
authors.lastname: Parsons
authors.forename: Cosma
authors.initials: C
authors.lastname: Spalluto
authors.forename: Angela F
authors.initials: AF
authors.lastname: Davies
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Knorz
authors.forename: Clare E G
authors.initials: CE
authors.lastname: Burlinson
authors.forename: Bee Ling
authors.initials: BL
authors.lastname: Ng
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Carter
authors.forename: Caroline Mackie
authors.initials: CM
authors.lastname: Ogilvie
authors.forename: David I
authors.initials: DI
authors.lastname: Wilson
authors.forename: Roland G
authors.initials: RG
authors.lastname: Roberts
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D007446:Chromosome Inversion; D002878:Chromosomes, Human, Pair 1; D002893:Chromosomes, Human, Pair 3; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein