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- Peyrard-Janvid, Myriam, et al.
(author)
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Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 94:1, s. 23-32
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Journal article (peer-reviewed)abstract
- Mutations in interferon regulatory factor 6 (IRF6) account for similar to 70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.
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- Berg, Ingrid, et al.
(author)
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Two modes of germline instability at human minisatellite MS1 (locus D1S7) : complex rearrangements and paradoxical hyperdeletion.
- 2003
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In: Am J Hum Genet. - 0002-9297. ; 72:6, s. 1436-47
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Journal article (peer-reviewed)abstract
- Minisatellite MS1 (locus D1S7) is one of the most unstable minisatellites identified in humans. It is unusual in having a short repeat unit of 9 bp and in showing somatic instability in colorectal carcinomas, suggesting that mitotic replication or repair errors may contribute to repeat-DNA mutation. We have therefore used single-molecule polymerase chain reaction to characterize mutation events in sperm and somatic DNA. As with other minisatellites, high levels of instability are seen only in the germline and generate two distinct classes of structural change. The first involves large and frequently complex rearrangements that most likely arise by recombinational processes, as is seen at other minisatellites. The second pathway generates primarily, if not exclusively, single-repeat changes restricted to sequence-homogeneous regions of alleles. Their frequency is dependent on the length of uninterrupted repeats, with evidence of a hyperinstability threshold similar in length to that observed at triplet-repeat loci showing expansions driven by dynamic mutation. In contrast to triplet loci, however, the single-repeat changes at MS1 exclusively involve repeat deletion, and can be so frequent--as many as 0.7-1.3 mutation events per sperm cell for the longest homogeneous arrays--that alleles harboring these long arrays must be extremely ephemeral in human populations. The apparently impossible existence of alleles with deletion-prone uninterrupted repeats therefore presents a paradox with no obvious explanation.
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