Analysis of the human Sonic Hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly

Vargas, Fernando; Roessler, Erich; Gaudenz, Karin; Belloni, Elena; Whitehead, Alexander S.; Kirke, Peader N.; Mills, James L.; Hooper, George F.; Stevenson, Roger E.; Cordeiro, Isabel; Correia, Patrícia; Félix, Têmis Maria; Gereige, Rani S.; Cunningham, Michael L.; Canún, Sonia; Antonarakis, Stylianos E.; Strachan, Tom; Tsui, Lap Chee; Scherer, Stephen W.; Muenke, Maximilian

doi:10.1007/s004390050709

Cited by 38 publications

(21 citation statements)

References 33 publications

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“…Furthermore, DNA degradation was present in some samples depending on the conditions of maintenance of the paper cards. Nevertheless, this study has provided reliable results in almost all cases, even in regions difficult to amplify, such as exon 1 and the last part of exon 3 of the SHH gene (Roessler et al 1996;Vargas et al 1998;Nanni et al 1999). Thus, we recommend the collection of biological material from newborn infants with birth defects in an effort to create DNA banks accessible to molecular genetics research in epidemiological studies.…”

Section: Discussionmentioning

confidence: 93%

“…We performed a mutational study by using single-strand conformational polymorphism (SSCP) analysis for the entire coding regions and exon-intron boundaries of SIX3 (8 primer pairs), SHH (6 primer pairs), TGIF (4 primer pairs), and ZIC2 (8 primer pairs) in 30 children with HPE. Primer pairs and polymerase chain reaction (PCR) conditions were as described elsewhere: SHH (Roessler et al 1996;Vargas et al 1998;Nanni et al 1999), ZIC2 (Brown et al 1998), SIX3 (Wallis et al 1999), TGIF (Gripp et al 2000). All of the PCRs were performed in a PTC-100 thermal cycler (MJ Research, Waltham, Mass.).…”

Section: Eclamc Dna Bankmentioning

confidence: 99%

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Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly

et al. 2001

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Holoprosencephaly (HPE) is genetically heterogeneous with four genes, SIX3, SHH, TGIF, and ZIC2 that have been identified to date and that are altered in 12% of patients. To analyze this prevalence in a South American population-based sample (57 HPE cases in 244,511 live and still births or 1 in 4300), we performed a mutational study of these genes in 30 unrelated children (26 newborns and 4 non-newborns) with HPE being ascertained by ECLAMC (Latin American Collaborative Study of Congenital Malformations). We identified three novel mutations: two were missense mutations of the SHH gene (Cys183-->Phe; His140-->Pro); the third mutation was a 2-bp deletion in the zinc-finger region of the ZIC2 gene. These molecular results explained 8% (2/26 newborn samples) of the HPE cases in this South American population-based sample, a proportion similar to our previously published data from a collection of cases.

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Section: Discussionmentioning

confidence: 93%

Section: Eclamc Dna Bankmentioning

confidence: 99%

Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly

et al. 2001

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“…Although SHH was once a strong candidate gene for sacral agenesis, mutations could not be found in both the coding region and 5Ј flanking region of SHH. 53,54 Instead, multiple mutations in the coding region of HLXB9 were found in patients with sacral agenesis. [5][6][7] The role of HLXB9 in sacral agenesis is however controversial because mice lacking Hlxb9 do not exhibit any defects in the development of sacral vertebrae and anorectal malformations.…”

Section: Discussionmentioning

confidence: 99%

Anorectal Malformations Caused by Defects in Sonic Hedgehog Signaling

Kim

Zhang

et al. 2001

The American Journal of Pathology

213

179

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Anorectal malformations are a common clinical problem affecting the development of the distal hindgut in infants. The spectrum of anorectal malformations ranges from the mildly stenotic anus to imperforate anus with a fistula between the urinary and intestinal tracts to the most severe form, persistent cloaca. The etiology, embryology, and pathogenesis of anorectal malformations are poorly understood and controversial. Sonic hedgehog (Shh) is an endoderm-derived signaling molecule that induces mesodermal gene expression in the chick hindgut. However, the role of Shh signaling in mammalian hindgut development is unknown. Here, we show that mutant mice with various defects in the Shh signaling pathway exhibit a spectrum of distal hindgut defects mimicking human anorectal malformations. Shh null-mutant mice display persistent cloaca. Mutant mice lacking Gli2 or Gli3, two zinc finger transcription factors involved in Shh signaling, respectively, exhibit imperforate anus with recto-urethral fistula and anal stenosis. Furthermore, persistent cloaca is also observed in Gli2 Anorectal malformations encompass a broad spectrum of congenital defects that frequently necessitates urgent surgical treatment in the newborn period, most often because of intestinal obstruction and sepsis. One of the most common anomalies, imperforate anus, has an incidence of 1 in 5000 and carries with it significant chronic morbidity, particularly with fecal incontinence. The most severe form of anorectal malformation, the cloacae, where distal intestinal and genitourinary tracts remain in a common channel, is much less common than imperforate anus (1 in 50,000) but has more significant serious longterm medical problems including gender assignment.

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“…Mutations in SHH, located in 7q35-q36, were shown to be responsible of holoprosencephaly, a developmental defect of the forebrain and midface [25]. Additional disorders linked to markers on the distal long arm of chromosome 7 include sacral agenesis [34], triphalangeal thumb, mirror polydactyly, polydactyly and tibial aplasia [35]. A sensorineural progressive form of deafness was recently mapped to chromosome 7q34-q36 [36].…”

Section: Chromosomal Localizationmentioning

confidence: 99%

ARP3β, the gene encoding a new human actin‐related protein, is alternatively spliced and predominantly expressed in brain neuronal cells

Jay

Bergé-Lefranc

Massacrier

et al. 2000

European Journal of Biochemistry

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A cDNA encoding a new human actin-related protein (ARP) was cloned. The corresponding protein is highly conserved with the previously described ARP3 protein, suggesting that it represents a second isoform of the human ARP3 subfamily. This new actin-related protein was subsequently named ARP3b and represents the second example of multiple isoforms of an actin-related protein in a single organism. The ARP3b gene was mapped to chromosome band 7q34, centromeric to Sonic Hedgehog. Gene structure analysis revealed that at least part of the observed ARP3b mRNA heterogeneity is caused by alternative splicing resulting in exon skipping. Transcripts produced after exon 2 skipping are predicted to encode truncated products, whose functionality is still unclear. An ARP3b pseudogene was detected on chromosome 2p11 by database searching. Several ARP3b mRNA species were detected by Northern blotting and their abundance varied importantly among tissues: the highest expression levels were detected in fetal and adult brain, whereas lower levels were observed in liver, muscle and pancreas. In contrast, ARP3 mRNAs were detected in all tissues tested. Using in situ hybridization, the expression of ARP3b in brain was shown to be restricted to neurons and epithelial cells from choroid plexus. This suggests a specific function for ARP3b in the physiology of the development and/or maintenance of distinct subsets of nerve cells.Keywords: actin-related protein; ARP3; cytoskeleton; nervous system. Actins are abundant, highly conserved proteins encoded by a multigene family. They polymerize to form filaments playing central roles in cell-shape maintenance, cell motility, cytokinesis and organelle movement. Recently, a group of proteins that are only distantly related to actin was discovered. These so called actin-related proteins (ARP) share only 35±55% amino acid identity with conventional actin. In most cases, ARPs contain one or several peptide insertions compared with actin and these insertions occur at positions such that they likely prevent polymerization [1]. ARP proteins and their corresponding genes have been numbered according to their amino acid identity and their insertions compared with actin [2]. The availability of the Saccharomyces cerevisiae full-length genome led to the discovery of seven new actin-related proteins, in addition to the previously described ARP1, ARP2 and ARP3 [3]. Orthologous ARPs from different species are highly conserved, whereas members of each class of ARP within a single species are not more similar to each other than to conventional actin. Each family might thus fulfill specific cellular functions.ARP1 is a component of a multiprotein complex which is required for dynein-based vesicle motility [4]. It is likely associated with centrosomes [5] and S. cerevisiae Arp1 null mutants have defects in mitotic spindle orientation and nuclear migration [6,7]. ARP2 (initially called ACT2) was first discovered in S. cerevisiae. As shown by null mutants analysis, ARP2 is required for completion of the cell cycle ...

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Analysis of the human Sonic Hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly

Cited by 38 publications

References 33 publications

Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly

Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly

Anorectal Malformations Caused by Defects in Sonic Hedgehog Signaling

ARP3β, the gene encoding a new human actin‐related protein, is alternatively spliced and predominantly expressed in brain neuronal cells

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