MNX1 (HLXB9) mutations in Currarino patients

Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Journal of Pediatric Surgery (Impact Factor: 1.39). 10/2009; 44(10):1892-8. DOI: 10.1016/j.jpedsurg.2009.03.039
Source: PubMed


The combination of partial absence of the sacrum, anorectal anomalies, and presacral mass constitutes Currarino syndrome (CS), which is associated with mutations in MNX1 motor neuron and pancreas homeobox 1 (previously HLXB9). Here, we report on the MNX1 mutations found in a family segregating CS and in 3 sporadic CS patients, as well as on the clinical characteristics of the affected individuals.
MNX1 mutations were identified by direct sequencing the coding regions, intron/exon boundaries of MNX1 in 5 CS Japanese family members and 3 Chinese sporadic cases and their parents.
There were 2 novel (P18PfsX37, R243W) and 2 previously described (W288G and IVS2 + 1G > A) mutations. These mutations were not found in 198 control individuals and are predicted to impair the functioning of the MNX1 protein.
The variability of the CS phenotype among related or unrelated patients bearing the same mutation advocates for differences in the genetic background of each individual and invokes the implication of additional CS susceptibility genes.

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    • "HLXB9 is a gene of 12,801 bp, is composed of 3 exons and codes for a transcription factor, HB9, formed by 401 aminoacids [29]. HB9 contains a homeodomain, preceded by a highly conserved region of 82 amino acids (159–241) and a region of polyalanine that expands from residue 121 to residue 134 in exon 1 [30]. "
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    ABSTRACT: Different parts of the genome occupy specific compartments of the cell nucleus based on the gene content and the transcriptional activity. An example of this is the altered nuclear positioning of the HLXB9 gene in leukaemia cells observed in association with its over-expression. This phenomenon was attributed to the presence of a chromosomal translocation with breakpoint proximal to the HLXB9 gene. Before becoming an interesting gene in cancer biology, HLXB9 was studied as a developmental gene. This homeobox gene is also known as MNX1 (motor neuron and pancreas homeobox 1) and it is relevant for both motor neuronal and pancreatic beta cells development. A spectrum of mutations in this gene are causative of sacral agenesis and more broadly, of what is known as the Currarino Syndrome, a constitutional autosomal dominant disorder. Experimental work on animal models has shown that HLXB9 has an essential role in motor neuronal differentiation. Here we present data to show that, upon treatment with retinoic acid, the HLXB9 gene becomes over-expressed during the early stages of neuronal differentiation and that this corresponds to a reposition of the gene in the nucleus. More precisely, we used the SK-N-BE human neuroblastoma cell line as an in vitro model and we demonstrated a transient transcription of HLXB9 at the 4th and 5th days of differentiation that corresponded to the presence, predominantly in the cell nuclei, of the encoded protein HB9. The nuclear positioning of the HLXB9 gene was monitored at different stages: a peripheral location was noted in the proliferating cells whereas a more internal position was noted during differentiation, that is while HLXB9 was transcriptionally active. Our findings suggest that HLXB9 can be considered a marker of early neuronal differentiation, possibly involving chromatin remodeling pathways.
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    ABSTRACT: The aim of the study was to review the degree to which the long-term outcome and ongoing morbidity in Currarino syndrome (CS) has been established. Analysis of previously published reports that have included long-term outcome data in CS and review of five additional patients with CS. Overall, long-term outcomes of children born with CS are not well described. Malignancy has been reported in six children of approximately 300 CS patients: four children with malignancy had a recurrence after primary excision. Malignancy has also occurred in four adults. Ongoing morbidity related to constipation, faecal incontinence, neurogenic bladder, urinary incontinence and presacral abscess, and more rarely meningitis, brain metastases, developmental delay and unusual gait. Almost certainly, previous reports have under-estimated the true incidence of these problems, given the methodology and focus of these series. There is paucity of information on the long-term outcomes in CS. Few authors have focused on ongoing symptoms, such that we speculate the true incidence of long-term urinary and bowel dysfunction may have been under-estimated in CS. Greater emphasis on the functional assessment of these systems during childhood may help predict the long-term outcome in CS. The most severe cases are diagnosed during infancy and childhood, and these are also the ones who are more likely to have ongoing long-term morbidity.
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