Acheiropodia Is Caused by a Genomic Deletion in C7orf2, the Human Orthologue of the Lmbr1 Gene

Ianakiev, Peter; Baren, Marijke J. van; Daly, Mark J.; Toledo, S. P. A.; Cavalcanti, Maria G.; Neto, Jordao C.; Silveira, Elizabeth Lemos; Freire‐Maia, Ademar; Heutink, Peter; Kilpatrick, M; Tsipouras, Petros

doi:10.1086/316955

Cited by 93 publications

(83 citation statements)

References 12 publications

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“…Affected individuals (who carry the same ancestral haplotype) show deletions in both LMBR1 alleles that remove exon 4 and Ϸ5-6 kb of surrounding genomic DNA. These data suggest that acheiropodia results from loss of function of the Lmbr1 gene (6). Based on our hypothesis that an Shh regulator resides in the Lmbr1 gene, we propose an alternative hypothesis.…”

Section: Discussionmentioning

confidence: 77%

“…Recent reports suggest that PPD constitutes one aspect of a complex disease locus. Acheiropodia (6), complex polysyndactyly (CPS) (7), and acropectoral syndrome (8) are all distinct, limb-specific disorders that map to this region, suggesting that elements essential for limb development are located in this locus.…”

Section: Preaxial Polydactyly (Ppd) Is a Common Limb Malformation In mentioning

confidence: 99%

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Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly

Lettice

Horikoshi

Heaney

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

416

378

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Preaxial polydactyly (PPD) is a common limb malformation in human.A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch (Ssq). The genetic lesions in both lie within the same respective intron of the LMBR1͞Lmbr1 gene, which resides Ϸ1 Mb away from Shh. Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh. This regulator is most likely the target for generating PPD mutations in human. )] is one of the most frequently observed human congenital limb malformations. Sporadic cases of PPD have been described, but most show an autosomal-dominant mode of inheritance. The limb-specific phenotype varies markedly within families, ranging from a simple addition of a phalanx in triphalangeal thumb to whole digit duplications and tibial aplasia. Using several large families, a PPD locus was mapped to a 450-kb region on chromosome 7q36, and all families described so far are linked to this locus (1-5). Recent reports suggest that PPD constitutes one aspect of a complex disease locus. Acheiropodia (6), complex polysyndactyly (CPS) (7), and acropectoral syndrome (8) are all distinct, limb-specific disorders that map to this region, suggesting that elements essential for limb development are located in this locus. Sasquatch (Ssq) is a mouse mutation that arose through a transgenic insertion (9). The mutation is semidominant, resulting in supernumerary preaxial (anterior) digits on the hindfeet in the heterozygotes. In homozygotes both fore-and hindlimbs show additional preaxial digits, and in some cases the long bones are shortened such that the limbs appear twisted. The insertion site responsible for the Ssq phenotype is physically linked to within Ϸ1 Mb of Shh.Here, we show that Ssq maps to the region on mouse chromosome 5 that corresponds to the human PPD locus. We identify mutations in a PPD patient and in the Ssq mouse. The PPD patient carries a de novo chromosomal translocation. Isolation of the PPD translocation breakpoint and the Ssq transgene insertion site revealed a similar location for these genetic disruptions within the Lmbr1 gene. We provide genetic analysis that shows that the Ssq mutation is not acting locally but in fact interrupts a long-range cis-acting regulator. This regulator operates on Shh residing 1.8 cM away, corresponding to a physical distance of Ϸ1 Mb. Consequently, disruption of Shh regulation is most likely the basis for PPD in humans. Materials and MethodsPatient Material. The translocation patient was clinically examined, and a member of her family was interviewed for family history at the Niigata University Hospital. All studies were approved by the local ethics committee. A member of the family gave written informed consent on behalf of the patient. The PPD families used in this study are...

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Section: Discussionmentioning

confidence: 77%

Section: Preaxial Polydactyly (Ppd) Is a Common Limb Malformation In mentioning

confidence: 99%

Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly

Lettice

Horikoshi

Heaney

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

416

378

View full text Add to dashboard Cite

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“…The studies of de novo reciprocal t(5,7)(q11,136) translocation and the acheiropody family with 4 -6 kb deletion containing LMBR1 exon 4 implied the presence of other limb-specific regulator of shh expression. 18,21 In our pedigree, the fact that all the coding regions and conserved regions were excluded from containing pathogenic mutation suggests that the other regulatory element could, if it exists, locate in unconserved regions. It seems likely that the only way to detect the proposed pathogenic mutation for our pedigree is to thoroughly sequence the remained unconserved regions in this 1.7 cM interval.…”

Section: Discussionmentioning

confidence: 93%

Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly

Wang

et al. 2008

Eur J Hum Genet

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Mutations in the long-range limb-specific cis-regulator (ZRS) could cause ectopic shh gene expression and are responsible for preaxial polydactyly (PPD). In this study, we analyzed a large Chinese isolated autosomal dominant PPD pedigree. By fine mapping and haplotype construction, we located the linked region to a 1.7 cM interval between flanking markers D7S2465 and D7S2423 of chromosome 7q36. We directly sequenced the candidate loci in this linked region, including the coding regions of the five genes (HLXB9, LMBR1, NOM1, RNF32 and C7orf13), the regulatory element (ZRS) of shh, the whole intron 5 of LMBR1 which contained the ZRS, and 18 conserved noncoding sequences (CNSs). Interestingly, no pathogenic mutation was identified. By using real-time quantitative PCR (qPCR), we also excluded the ZRS duplication in this pedigree. Our results indicate that, at least, it is not the mutation in a functional gene, CNS region or duplication of ZRS that cause the phenotype of this pedigree. The etiology of this PPD family still remains unclear and the question whether another limb-specific regulatory element of shh gene exists in the noncoding region in this 1.7 cM interval remains open for future research.

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“…They include preaxial polydactyly (Hing et al 1995;Heus et al 1999;Zguricas et al 1999), complex polysyndactyly (Tsukurov et al 1994), triphalangeal thumb (Heutink et al 1994;Radhakrishna et al 1996;Balci et al 1999) and acheiropodia (Ianakiev et al 2001).…”

Section: Resultsmentioning

confidence: 99%

A syndactyly type IV locus maps to 7q36

Sato

Pan

et al. 2007

J Hum Genet

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Syndactyly occurs as an isolated abnormality or a part of a malformation syndrome. Syndactyly types I, II, III and V have been mapped to chromosomal regions 2q34-q36, 2q31-q32, 6q21-q23.2 and 2q31-q32, respectively, whereas syndactyly type IV (SD4) is extremely rare, and its gene localization has not yet been assigned. The SD4 manifests complete syndactyly of all fingers accompanied with polydactyly, and flexion of the fingers gives the hand a cup-shaped appearance. We performed a linkage and haplotype analysis of a Chinese pedigree with autosomal dominant, non-syndromic SD4 using a set of 406 microsatellite markers. The analysis gave the maximum two-point LOD score of 1.613 at recombination fraction of 0.00 and penetrance of 1.00. Thus, the SD4 locus in the family was likely assigned to a 17.39-cM region at a segment between markers D7S3070 and D7S559 at 7q36, although the LOD score obtained was not high enough to conclude the localization. Analysis of three candidate genes, LMBR1, SHH and ZRS, failed to identify any pathogenic mutations. Our gene mapping may give a clue to identify the putative SD4 gene and provide a better understanding of normal human limb development.

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Acheiropodia Is Caused by a Genomic Deletion in C7orf2, the Human Orthologue of the Lmbr1 Gene

Cited by 93 publications

References 12 publications

Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly

Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly

Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly

A syndactyly type IV locus maps to 7q36

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