Alternative titles; symbols
HGNC Approved Gene Symbol: GRHL3
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38) : 1:24,319,357-24,364,482 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | van der Woude syndrome 2 | 606713 | Autosomal dominant | 3 |
SOM belongs to a family of transcription factors related to the Drosophila grainyhead (grh) protein. In Drosophila, grainyhead has a role in early dorsal/ventral patterning and in later organ and tissue development.
By searching a genomic database using the dimerization domains of mammalian grainyhead (MGR, or GRHL1; 609786), and brother of MGR (BOM, or GRHL2; 608576) as queries, followed by PCR and 5-prime RACE of tonsil and testis cDNA libraries, Ting et al. (2003) cloned SOM. Genomic sequence analysis, database analysis, and RT-PCR indicated that there are 3 SOM splice variants, which the authors designated SOM1, SOM2, and SOM3. The longest variant, SOM1, encodes a deduced 607-amino acid protein containing an N-terminal activation domain, a central DNA-binding domain, and a C-terminal dimerization domain. It shares 90% amino acid identity with mouse Som, and more than 60% amino acid similarity with MGR and BOM. The SOM2 variant contains an alternate first coding exon compared with SOM1. The SOM3 variant lacks exon 2, which encodes a significant component of the transactivation domain. Northern blot analysis detected a single 3.0-kb band, consistent with the predicted sizes of all 3 SOM transcripts, in placenta and kidney. RT-PCR using transcript-specific primers detected SOM1 expression in brain, pancreas, testis, placenta, prostate, colon, and kidney; SOM2 expression in brain, pancreas, placenta, kidney, tonsil, and thymus; and SOM3 expression in brain, pancreas, and testis.
Ting et al. (2003) determined that the SOM gene contains 8 exons, including 2 alternate first coding exons, and spans about 20 kb.
Hartz (2003) mapped the SOM gene to chromosome 1p36.11 based on an alignment of the SOM sequence (GenBank AK074386) with the genomic sequence.
By database analysis, Ting et al. (2003) mapped the mouse Grhl3 gene to chromosome 4.
By yeast 2-hybrid assay of the isolated dimerization domains of SOM and other grainyhead-like proteins, Ting et al. (2003) determined that SOM can form homodimers and heterodimers with MGR and BOM, but not with other grainyhead-like proteins. The isolated transactivation domains of SOM1 and SOM2 were active in a reporter assay, but the N-terminal sequence of SOM3, which lacks the transactivation domain, was not.
By in situ hybridization, Ting et al. (2003) detected Grhl3 expression at mouse embryonic day (E) 8.5 in the nonneural ectoderm immediately adjacent to the neural plate, which was undergoing folding to form the neural tube. At later time points, more widespread expression was observed in the surface ectoderm, as well as in other tissues lined by squamous epithelium, including the oral cavity, urogenital sinus, and anal canal. Expression progressively increased until E15.5.
Using ATAC-seq analysis, Jacobs et al. (2018) profiled open chromatin across a cohort of inbred Drosophila strains, and found that a Grh-binding site can causally determine the in vivo accessibility of an enhancer-sized region, predicting the presence of potential chromatin regulators for chromatin accessibility. In Drosophila eye-antennal discs, evaluation of the occupancy of Grh-binding sites showed that whenever a region with a Grh motif was accessible, Grh was stably bound there, suggesting that Grh plays a key role in the accessible chromatin landscape of epithelial cells. Further analysis showed that Grh-binding sites are necessary for enhancer accessibility, and Grh binding opens its target enhancers but does not directly activate them. Evolutionary conservation analysis identified some candidate co-transcription factors such as Atonal (Ato; see 601461), indicating that the activity of enhancers primed through Grh binding requires the recruitment of additional factors. Loss-of-function and gain-of-function experiments showed that deletion of Grh causes the loss of DNA accessibility but ectopic expression recovers it, demonstrating that Grh is a 'pioneer factor' that is sufficient to directly and specifically open its target regions in different tissues. Investigation of the local sequence context around the Grh motifs revealed that, like other pioneer factors, Grh preferentially binds to DNA sites in regions that have a high intrinsic affinity for nucleosomes. Jacobs et al. (2018) showed that the 3 Grh-like transcription factors GRHL1, GRHL2, and GRHL3 have similar functions in human cells.
By targeted exome sequencing in 8 affected and 3 unaffected members of a large Finnish pedigree with van der Woude syndrome mapping to chromosome 1p34 (VWS2; 606713), Peyrard-Janvid et al. (2014) identified heterozygosity for a 2-bp insertion in the GRHL3 gene (608317.0001) that segregated with disease in the family and was not found in controls. Screening of 44 additional VWS families who were negative for causative mutations in the IRF6 gene (607199) revealed heterozygous GRHL3 mutations in 7 of them (see, e.g., 608317.0002-608317.0005).
Associations Pending Confirmation
For discussion of a possible association between variation in GRHL3 and nonsyndromic cleft palate, see 606713.
Seller and Adinolfi (1981) described 'curly tail' (ct), a semidominant mutation in mouse that causes predominantly low spinal neural tube defects (NTDs). Seller (1994) reported that exogenous myoinositol reduces NTD in curly tail mice. The penetrance of ct is markedly affected by other genes, including mct1 on mouse chromosome 17 (Letts et al., 1995) and Pax3 (606597) on mouse chromosome 1 (Estibeiro et al., 1993).
Neumann et al. (1994) mapped the curly tail phenotype to distal mouse chromosome 4, which is equivalent to 1p36-1pter in humans.
Greene and Copp (1997) noted that alterations in penetrance and expressivity of curly tail result from environmental factors including retinoic acid, mitomycin, hydroxyurea, and fluorouracil; however, unlike in humans, folate and methionine did not appear to have an effect. Greene and Copp (1997) found that intraperitoneal injection of pregnant female mice with myoinositol at various times during the critical phase of neural tube closure decreased the frequency of spina bifida in developing embryos. A single injection on embryonic day 9.5 reduced NTD frequency by 70% in ct mice. The authors demonstrated further that inositol increased the flux through the inositol/lipid cycle, stimulated protein kinase C (see PRKCA; 176960) activity, and upregulated expression of retinoic acid receptor beta (RARB; 180220).
Cogram et al. (2004) investigated the molecular mechanism by which inositol prevents mouse NTDs. They examined neurulation-stage embryos for PKC expression and applied PKC inhibitors to curly tail embryos developing in culture. Application of peptide inhibitors to neurulation-stage embryos revealed an absolute dependence on the activity of PRKCB1 (176970) and PRKCG (176980) for prevention of NTDs by inositol, and partial dependence on PRKCZ (176982), whereas PRKCA, PRKCB2 (see 176970), PRKCD (176977), and PRKCE (176975) were dispensable. Defective proliferation of hindgut cells was a key component of the pathogenic sequence leading to NTDs in curly tail. Hindgut cell proliferation was stimulated specifically by inositol, an effect that required activation of PRKCB1. Cogram et al. (2004) proposed an essential role for PRKCB1 and PRKCG in mediating the prevention of mouse NTDs by inositol.
Ting et al. (2003) found that transgenic Grhl3-null mouse embryos displayed neural tube defects, including thoracolumbosacral spina bifida and curled tail, as well as spinal skeletal abnormalities such as kyphosis, splayed spinal processes, and lack of vertebral arch formation. Spina bifida was caused by a primary failure of neural tube closure. Ting et al. (2003) noted that the phenotype of the Grhl3-null mice is similar to that of the curly tail mouse. The authors found that the mouse Grhl3 locus maps to the same 13-Mb contiguous sequence on chromosome 4 as the ct locus, and that Grhl3 mRNA expression in curly tail mice is decreased to about 30% of normal. However, there were some phenotypic differences; most notably, whereas curly tail mice respond to inositol treatment, such treatment had no effect on the severity and incidence of spina bifida in Grhl3-null embryos, and genetic complementation mice (Grhl3-/ct) had a higher incidence of spina bifida than reported for curly tail homozygotes. Ting et al. (2003) concluded that Grhl3 and ct may regulate one another, be allelic, or be involved in the same pathway, and suggested that Grhl3 is a good candidate for the gene underlying the curly tail phenotype.
The Drosophila cuticle is essential for maintaining the surface barrier defenses of the fly. Integral to cuticle resilience is the transcription factor grainyhead, which regulates production of the enzyme required for covalent crosslinking of the cuticular structural components. Ting et al. (2005) reported that formation and maintenance of the epidermal barrier in mice are dependent on a mammalian homolog of grainyhead, grainyhead-like-3. Mice lacking this factor display defective skin barrier function and deficient wound repair accompanied by reduced expression of transglutaminase-1 (190195), the key enzyme involved in crosslinking the structural components of the superficial epidermis. Ting et al. (2005) concluded that the functional mechanism involving protein crosslinking that maintain the epidermal barrier and induce tissue repair are conserved across 700 million years of evolution.
Peyrard-Janvid et al. (2014) assayed the effect of GRHL3 mutations on Grhl3 function in zebrafish and observed abrogation of periderm development, consistent with a dominant-negative effect. In mouse, all 6 embryos lacking Grhl3 exhibited abnormal oral periderm and 1 (17%) developed cleft palate. Analysis of the oral phenotype of double-heterozygote (Irf6 +/-; Grhl3 +/-) murine embryos failed to demonstrate epistasis between the 2 genes, suggesting that they function in separate but convergent pathways during palatogenesis.
In affected members of a large Finnish pedigree with van der Woude syndrome (VWS2; 606713), originally studied by Koillinen et al. (2001), Peyrard-Janvid et al. (2014) identified heterozygosity for a 2-bp insertion (c.970_971insTG) in exon 8 of the GRHL3 gene, causing a frameshift predicted to result in a premature termination codon (Phe324LeufsTer22) within the DNA-binding domain. The mutation segregated with disease in the family and was not found in 561 Finnish controls.
In a Swedish male patient with van der Woude syndrome (VWS2; 606713), who exhibited lip pits and cleft palate and had been studied by Peyrard-Janvid et al. (2005), Peyrard-Janvid et al. (2014) identified heterozygosity for a de novo 4-bp deletion (c.1559_1562delGGAG) in exon 14 of the GRHL3 gene, causing a frameshift predicted to result in a premature termination codon (Glu522LeufsTer10) within the dimerization domain.
In a Pakistani male patient with van der Woude syndrome (VWS2; 606713), who exhibited cleft lip/palate and lip pits and previously had been studied by Malik et al. (2010), Peyrard-Janvid et al. (2014) identified heterozygosity for a c.893G-A transition in exon 7 of the GRHL3 gene, resulting in an arg298-to-his (R298H) substitution within the DNA-binding domain. Peyrard-Janvid et al. (2014) noted that Malik et al. (2010) had identified a missense variant (K80R) in the IRF6 gene (607199) in this patient, which was not conclusively determined to be causative, raising the possibility that variants in both IRF6 and GRHL3 could contribute to VWS in a family.
In 7 affected individuals over 3 generations of a large family from the United Kingdom with van der Woude syndrome (VWS2; 606713), Peyrard-Janvid et al. (2014) identified heterozygosity for a c.1419+1G-T transversion in intron 11 of the GRHL3 gene. The phenotype in this family ranged from lip pits alone to lip pits plus cleft palate with or without a uvular anomaly. One patient also exhibited anodontia.
In a Filipino male patient with van der Woude syndrome (VWS2; 606713), who had cleft lip/palate and lip pits, Peyrard-Janvid et al. (2014) identified heterozygosity for a de novo c.1171C-T transition in exon 9 of the GRHL3 gene, resulting in an arg391-to-cys (R391C) substitution within the DNA-binding domain.
Cogram, P., Hynes, A., Dunlevy, L. P. E., Greene, N. D. E., Copp, A. J. Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol. Hum. Molec. Genet. 13: 7-14, 2004. [PubMed: 14613966] [Full Text: https://doi.org/10.1093/hmg/ddh003]
Estibeiro, J. P., Brook, F. A., Copp, A. J. Interaction between splotch (Sp) and curly tail (ct) mouse mutants in the embryonic development of neural tube defects. Development 119: 113-121, 1993. [PubMed: 8275849] [Full Text: https://doi.org/10.1242/dev.119.1.113]
Greene, N. D. E., Copp, A. J. Inositol prevents folate-resistant neural tube defects in the mouse. Nature Med. 3: 60-66, 1997. [PubMed: 8986742] [Full Text: https://doi.org/10.1038/nm0197-60]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/3/2003.
Jacobs, J., Atkins, M., Davie, K., Imrichova, H., Romanelli, L., Christiaens, V., Hulselmans, G., Potier, D., Wouters, J., Taskiran, I. I., Paciello, G., Gonzalez-Blas, C. B., Koldere, D., Aibar, S., Halder, G., Aerts, S. The transcription factor grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes. Nature Genet. 50: 1011-1020, 2018. [PubMed: 29867222] [Full Text: https://doi.org/10.1038/s41588-018-0140-x]
Koillinen, H., Wong, F. K., Rautio, J., Ollikainen, V., Karsten, A., Larson, O., Teh, B. T., Huggare, J., Lahermo, P., Larsson, C., Kere, J. Mapping of the second locus for the Van der Woude syndrome to chromosome 1p34. Europ. J. Hum. Genet. 9: 747-752, 2001. [PubMed: 11781685] [Full Text: https://doi.org/10.1038/sj.ejhg.5200713]
Letts, V. A., Schork, N. J., Copp, A. J., Bernfield, M., Frankel, W. N. A curly-tail modifier locus, mct1, on mouse chromosome 17. Genomics 29: 719-724, 1995. [PubMed: 8575765] [Full Text: https://doi.org/10.1006/geno.1995.9946]
Malik, S., Kakar, N., Hasnain, S., Ahmad, J., Wilcox, E. R., Naz, S. Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan. Clin. Genet. 78: 247-256, 2010. [PubMed: 20184620] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01375.x]
Neumann, P. E., Frankel, W. N., Letts, V. A., Coffin, J. M., Copp, A. J., Bernfield, M. Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice. Nature Genet. 6: 357-362, 1994. [PubMed: 8054974] [Full Text: https://doi.org/10.1038/ng0494-357]
Peyrard-Janvid, M., Leslie, E. J., Kousa, Y. A., Smith, T. L., Dunnwald, M., Magnusson, M., Lentz, B. A., Unneberg, P., Fransson, I., Koillinen, H. K., Rautio, J., Pegelow, M., and 9 others. Dominant mutations in GRHL3 cause Van der Woude syndrome and disrupt oral periderm development. Am. J. Hum. Genet. 94: 23-32, 2014. [PubMed: 24360809] [Full Text: https://doi.org/10.1016/j.ajhg.2013.11.009]
Peyrard-Janvid, M., Pegelow, M., Koillinen, H., Larsson, C., Fransson, I., Rautio, J., Hukki, J., Larson, O., Karsten, A. L.-A., Kere, J. Novel and de novo mutations of the IRF6 gene detected in patients with Van der Woude or popliteal pterygium syndrome. Europ. J. Hum. Genet. 13: 1261-1267, 2005. [PubMed: 16160700] [Full Text: https://doi.org/10.1038/sj.ejhg.5201493]
Seller, M. J., Adinolfi, M. The curly-tail mouse: an experimental model for human neural tube defects. Life Sci. 29: 1607-1615, 1981. [PubMed: 7031395] [Full Text: https://doi.org/10.1016/0024-3205(81)90061-8]
Seller, M. J. Vitamins, folic acid and the cause and prevention of neural tube defects. Ciba Found. Symp. 181: 161-173, 1994. [PubMed: 8005023] [Full Text: https://doi.org/10.1002/9780470514559.ch10]
Ting, S. B., Caddy, J., Hislop, N., Wilanowski, T., Auden, A., Zhao, L., Ellis, S., Kaur, P., Uchida, Y., Holleran, W. M., Elias, P. M., Cunningham, J. M., Jane, S. M. A homolog of Drosophila grainy head is essential for epidermal integrity in mice. Science 308: 411-413, 2005. [PubMed: 15831758] [Full Text: https://doi.org/10.1126/science.1107511]
Ting, S. B., Wilanowski, T., Auden, A., Hall, M., Voss, A. K., Thomas, T., Parekh, V., Cunningham, J. M., Jane, S. M. Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3. Nature Med. 9: 1513-1519, 2003. [PubMed: 14608380] [Full Text: https://doi.org/10.1038/nm961]
Ting, S. B., Wilanowski, T., Cerruti, L., Zhao, L.-L., Cunningham, J. M., Jane, S. M. The identification and characterization of human Sister-of-Mammalian Grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors. Biochem. J. 370: 953-962, 2003. [PubMed: 12549979] [Full Text: https://doi.org/10.1042/BJ20021476]