Involvement of the HLXB9 Homeobox Gene in Currarino Syndrome

Belloni, Elena; Martucciello, G.; Verderio, D.; Ponti, E.; Seri, Marco; Jasonni, Vincenzo; Torre, Michele; Ferrari, Maurizio; Tsui, Lap Chee; Scherer, Stephen W.

doi:10.1086/302723

Cited by 140 publications

(136 citation statements)

References 17 publications

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“…21,22 However, no mutation has been reported within the region encoding the polyalanine repeat in HB9, so far, and variation in length is not associated with the presence of Currarino syndrome. 16 In summary, several conclusions can be drawn from this study.…”

Section: European Journal Of Human Geneticsmentioning

confidence: 62%

“…Three mutations have been described 4912 C4T (R52W), 4915 C4T (R53W) and 4916 G4A (R53Q), which alter one of the two arginine residues at positions 52 or 53 within the NLS motif. 6,16 Mutation of both residues in PDX-1 result in complete cytoplasmic retention. 17 Thus, these residues may also play a role for nuclear translocation of HB9 and the above mentioned HLXB9 missense mutations potentially reduce nuclear translocation of HB9.…”

Section: European Journal Of Human Geneticsmentioning

confidence: 99%

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Spectrum of mutations and genotype–phenotype analysis in Currarino syndrome

2001

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The triad of a presacral tumour, sacral agenesis and anorectal malformation constitutes the Currarino syndrome which is caused by dorsal-ventral patterning defects during embryonic development. The syndrome occurs in the majority of patients as an autosomal dominant trait associated with mutations in the homeobox gene HLXB9 which encodes the nuclear protein HB9. However, genotype ± phenotype analyses have been performed only in a few families and there are no reports about the specific impact of HLXB9 mutations on HB9 function. We performed a mutational analysis in 72 individuals from nine families with Currarino syndrome. We identified a total of five HLXB9 mutations, four novel and one known mutation, in four out of four families and one out of five sporadic cases. Highly variable phenotypes and a low penetrance with half of all carriers being clinically asymptomatic were found in three families, whereas affected members of one family showed almost identical phenotypes. However, an obvious genotype ± phenotype correlation was not found. While HLXB9 mutations were diagnosed in 23 patients, no mutation or microdeletion was detected in four sporadic patients with Currarino syndrome. The distribution pattern of here and previously reported HLXB9 mutations indicates mutational predilection sites within exon 1 and the homeobox. Furthermore, sequence homology to Drosophila homeobox genes suggest that some of these mutations located within the homeobox may alter the DNA-binding specificity of HB9 while those in sequences homologous to a recently identified NLS motif of the human homeobox gene PDX-1 may impair nuclear translocation of the mutated protein. European Journal of Human Genetics (2001) 9, 599 ± 605.

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Section: European Journal Of Human Geneticsmentioning

confidence: 62%

Section: European Journal Of Human Geneticsmentioning

confidence: 99%

Spectrum of mutations and genotype–phenotype analysis in Currarino syndrome

2001

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“…The homeobox gene HLXB9 (Genbank #142994) is mutated in the Currarino triad (OMIM #176450), which is composed of dominantly inherited anorectal and GU malformations, a presacral mass, and partial sacral agenesis (Currarino and Weisbruch, 1989;Currarino, 1996;Belloni et al, 2000;McKusick, 2002). The observed pattern of anomalies can be explained by a malformation in the caudal portion of the notochord, resulting in aberrant secondary neurulation.…”

Section: Discussionmentioning

confidence: 99%

Urorectal septum malformation sequence: Insights into pathogenesis

Mauch

Albertine

2002

Anat. Rec.

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We characterize the urorectal septum malformation sequence (URSMS) in discordant fetal lambs and relate it to the human syndromes with which URSMS is associated. We found abnormal external genitalia, imperforate anus, and fistulous connections between the rectum, bladder, and vagina. Discordance among the dizygous twins eliminated teratogens as a likely etiologic factor. We summarize the relevant literature and propose a molecular model for the pathogenesis of the URSMS, in which alterations in sonic hedgehog and homeobox genes lead to caudal mesodermal deficiency during blastogenesis. Anat Rec 268: 405-410, 2002.

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“…The commonest and least severe defect is anal stenosis -the narrowing of the anal opening. More severe is the imperforate anus, which (Belloni et al, 2000, Hagan et al, 2000, Hall et al, 1980, Kohlhase et al, 1998, Martinez-Frias et al, 2001, Rittler et al, 1996, Ross et al, 1998. Animal models for various digestive system malformations have been developed to investigate their genetic and environmental basis.…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signalling is required for cloacal development in the zebrafish embryo

Parkin¹,

Allen²,

Ingham³

2009

Int. J. Dev. Biol.

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The Hedgehog (Hh) family of signalling molecules is essential for a wide range of developmental processes. Mammalian studies have implicated the Hedgehog pathway in the aetiology of anorectal malformations (ARMs), relatively common congenital anomalies caused by failures in the development of the cloaca. In this study we demonstrate that Hh signalling is absolutely required for the formation of the zebrafish cloaca and that the severity of the posterior gut abnormalities induced by a reduction in Hh activity is dependent on the levels of Hh signal transduction. The complete loss of all Hh activity results in the most severe defects and the critical period for Hh activity is between 34 and 74 hours post fertilisation. Using a range of mutant genotypes that cause notochord and floorplate abnormalities, we show that the source of the Hh signals required for posterior gut formation is the endoderm and not the notochord, as previously postulated in mammalian models of ARMs. We show that Adriamycin, a drug known to cause ARMs in rat, but not chick embryos, has no effect on the development of the zebrafish gastrointestinal tract. These studies establish the zebrafish as a model for ARMs, and for the elucidation of other pathways involved in hindgut developmental processes.

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Involvement of the HLXB9 Homeobox Gene in Currarino Syndrome

Cited by 140 publications

References 17 publications

Spectrum of mutations and genotype–phenotype analysis in Currarino syndrome

Spectrum of mutations and genotype–phenotype analysis in Currarino syndrome

Urorectal septum malformation sequence: Insights into pathogenesis

Hedgehog signalling is required for cloacal development in the zebrafish embryo

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