Fine Mapping of the Split-Hand/Split-Foot Locus (SHFM3) at 10q24: Evidence for Anticipation and Segregation Distortion

Özen, Rýdvan S.; Baysal, Bora E.; Devlin, Bernie; Farr, Joan E.; Gorry, Michael; Ehrlich, Garth D.; Richard, Charles W.

doi:10.1086/302403

Cited by 35 publications

(47 citation statements)

References 46 publications

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“…The dactylaplasia mouse is an ideal phenotypic and genotypic model for human ectrodactyly (SHFM3) because the responsible SHFM3 locus on human 10q24 is homologous to the Dac locus on mouse chromosome 19 (2,(6)(7)(8)(9). Recently, genomic rearrangements have been identified in several unrelated SHFM3 families (10-13).…”

Section: Discussionmentioning

confidence: 99%

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

Kano

Kurahashi

Toda

2007

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

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Dactylaplasia, characterized by missing central digital rays, is an inherited mouse limb malformation that depends on two genetic loci. The first locus, Dac, is an insertional mutation around the dactylin gene that is inherited as a semidominant trait. The second locus is an unlinked modifier, mdac/Mdac, that is polymorphic among inbred strains. Mdac dominantly suppresses the dactylaplasia phenotype in mice carrying Dac. However, little is known about either locus or the nature of their interaction. Here we show that Dac is a LTR retrotransposon insertion caused by the type D mouse endogenous provirus element (MusD). This insertion exhibits different epigenetic states and spatiotemporally expresses depending on the mdac/Mdac modifier background. In dactylaplasia mutants (Dac/؉ mdac/mdac), the LTRs of the insertion contained unmethylated CpGs and active chromatin. Furthermore, MusD elements expressed ectopically at the apical ectodermal ridge of limb buds, accompanying the dactylaplasia phenotype. On the other hand, in Dac mutants carrying Mdac (Dac/؉ Mdac/mdac), the 5 LTR of the insertion was heavily methylated and enriched with inactive chromatin, correlating with inhibition of the dactylaplasia phenotype. Ectopic expression was not observed in the presence of Mdac, which we refined to a 9.4-Mb region on mouse chromosome 13. We report a pathogenic mutation caused by MusD. Our findings indicate that ectopic expression from the MusD insertion correlates with the dactylaplasia phenotype and that Mdac acts as a defensive factor to protect the host genome from pathogenic MusD insertions.dactylin ͉ ectrodactyly ͉ LTR ͉ split hand/split foot malformation ͉ methylation D actylaplasia is an inherited mouse limb malformation that is characterized by missing central digital rays. The Dac mutation is inherited as a semidominant trait, evidenced by missing central digits in the fore-and hindlimbs of heterozygous mice and monodactyly in homozygous mice (1, 2). The Dac locus has been mapped to the distal end of chromosome 19. Two independent Dac mutant alleles, Dac 1J and Dac 2J , arose spontaneously in breeding colonies. Both are insertions residing within the same locus: Dac 1J is located in the region upstream of the dactylin gene, and Dac 2J is located in intron 5 of dactylin (3). Southern blot analysis indicated that both insertions are larger than 4.5 kb; however, ''jumping PCR'' identified only the LTR portion of the insertion (3). Partial PCR products terminating in the 5Ј and 3Ј LTRs cross-prime each other, resulting in amplified products that lack any of the internal sequence between LTRs. Therefore, these insertions were thought to be caused by an early transposon (ETn) element, which is a common mutagen in mice (4, 5).Split hand/split foot malformation (SHFM) in humans is a congenital limb malformation that has an ectrodactyly phenotype analogous to that of the dactylaplasia mouse. SHFM is genetically heterogeneous; to date, five different loci, SHFM1 to SHFM5, have been mapped. Dactylaplasia is a mouse model of S...

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Section: Discussionmentioning

confidence: 99%

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

Kano

Kurahashi

Toda

2007

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

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“…The SHFM3 locus was identified by linkage mapping to chromosome 10q in multiple families with isolated SHFM [Nunes et al, 1995;Gurrieri et al, 1996;Raas-Rothschild et al, 1996;Ozen et al, 1999]. Notably, this locus in humans was known to be syntenic to the locus in mice causing the Dactylaplasia (Dac) phenotype, which comprises absence of the central digits with clefts or monodactyly and thus closely resembles human SHFM.…”

Section: Recurrent Genomic Duplicationsmentioning

confidence: 99%

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

Gurrieri

Everman

2013

American J of Med Genetics Pt A

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We here provide an update on the clinical, genetic, and molecular aspects of split-hand/foot malformation (SHFM). This rare condition, affecting 1 in 8,500-25,000 newborns, is extremely complex because of its variability in clinical presentation, irregularities in its inheritance pattern, and the heterogeneity of molecular genetic alterations that can be found in affected individuals. Both syndromal and nonsyndromal forms are reviewed and the major molecular genetic alterations thus far reported in association with SHFM are discussed. This updated overview should be helpful for clinicians in their efforts to make an appropriate clinical and genetic diagnosis, provide an accurate recurrence risk assessment, and formulate a management plan.

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“…2,3 SHFM is highly heterogeneous. Linkage or cytogenetic analysis of the nonsyndromic forms in humans has revealed six different loci for SHFM1-6 types: chromosome 7q21.2-q21.3 (SHFM1, MIM 183600), 4,5 Xq26 (SHFM2, MIM 313350), 6 10q24 (SHFM3, MIM 600095), [7][8][9][10] 3q27 (SHFM4, MIM 605289), 1 2q31 (SHFM5, MIM 606708) 11,12 and 12q13 (SHFM6, MIM 225300). 13,14 SHFM1, 3, 4 and 5 exhibit autosomal-dominant inheritance; SHFM6 exhibits autosomal-recessive transmission; SHFM2 exhibits X-linked inheritance pattern.…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation

et al. 2014

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Split-hand/foot malformation (SHFM) is a congenital limb deformity due to the absence or dysplasia of central rays of the autopod. Six SHFM loci have already been identified. Here we describe a Chinese family with autosomal-dominant SHFM1 that has previously been mapped to 7q21.2-21.3. The two affected family members, mother and son, showed deep median clefts between toes, ectrodactyly and syndactyly; the mother also showed triphalangeal thumbs. Exome sequencing and variant screening of candidate genes in the six loci known to be responsible for SHFM revealed a novel heterozygous mutation, c.558G4T (p. (Gln186His)), in distal-less homeobox 5 (DLX5). As DLX5 encodes a transcription factor capable of transactivating MYC, we also tested whether the mutation could affect DLX5 transcription acitivity. Results from luciferase reporter assay revealed that a mutation in DLX5 compromised its transcriptional activity. This is the first report of a mutation in DLX5 leading to autosomal-dominant SHFM1.

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Fine Mapping of the Split-Hand/Split-Foot Locus (SHFM3) at 10q24: Evidence for Anticipation and Segregation Distortion

Cited by 35 publications

References 46 publications

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation

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