Alternative titles; symbols
HGNC Approved Gene Symbol: YY1AP1
SNOMEDCT: 717824007;
Cytogenetic location: 1q22 Genomic coordinates (GRCh38) : 1:155,659,442-155,688,996 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q22 | Grange syndrome | 602531 | Autosomal recessive | 3 |
By differential display PCR of normal hepatic tissue and hepatocellular carcinomas, followed by screening a placenta cDNA library, Wang et al. (2001) cloned YY1AP1, which they called HCCA2. The deduced 467-amino acid protein has a calculated molecular mass of 50.65 kD. HCCA2 contains 2 SH3-binding domains, 2 N-glycosylation sites, 6 N-myristoylation sites, and numerous phosphorylation sites, but it does not have a transmembrane domain, signal peptide, or targeting sequences. Northern blot analysis detected 1.8- and 2.5-kb transcripts in all adult tissues examined except liver. Expression was also detected in fetal liver, lung, brain, and spleen. Western blot analysis of transfected embryonic kidney fibroblasts detected HCCA2 at an apparent molecular mass of about 50 kD. Immunohistochemical staining showed that HCCA2 protein was localized in the cytoplasm of liver cancer tissues, and it was not found in surrounding nontumor hepatocytes.
Kuryshev et al. (2006) found that the deduced YY1AP1 protein contains 750 amino acids, 748 of which correspond to amino acids 590 to 1,337 of the GON4L protein (610393). The last 2 C-terminal residues of YY1AP1 come from the long terminal repeat of MER51A. RT-PCR detected ubiquitous expression of YY1AP1, with highest levels in testis and skeletal muscle.
Guo et al. (2017) fractionated lysates of smooth muscle cells (SMCs) and HeLa cells and detected YY1AP1 in the nuclear fraction. Immunofluorescence confirmed the nuclear localization of YY1AP1 in SMCs and demonstrated staining throughout the nucleoplasm, along with localized staining that overlapped with immunostaining of a nucleolus marker. Immunohistochemical staining of a control human carotid artery showed that YY1AP1 was present in the nuclei of SMCs between elastin lamellae, and cells in neointimal lesions in the lumen and endothelial cells of the vasa vasorum also showed YY1AP1 nuclear staining.
Kuryshev et al. (2006) determined that YY1AP1 was formed by fusion of the 5-prime region of the ASH1L gene (607999) and the 3-prime region of the GON4L gene (610393) during a tandem segmental duplication on chromosome 1. YY1AP1 contains the partial promoter and untranslated first exon of ASH1L and coding exons 13 to 21 of GON4L. The 3-prime region of YY1AP1 originated from a long terminal repeat of an endogenous retrovirus, known as the MER51A repeat, that was inserted into exon 21 of GON4L after the duplication.
By genomic sequence analysis, Kuryshev et al. (2006) mapped the YY1AP1 gene to chromosome 1q22.
Wang et al. (2001) determined that HCCA2 was not expressed in normal adult liver tissue, but it was expressed in 79% of hepatocellular carcinomas tested. HCCA2 expression was associated with invasion of the tumor capsule.
Guo et al. (2017) determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Studies in vascular smooth muscle cells showed that loss of YY1AP1 results in cell cycle arrest, with decreased proliferation and increased levels of the cell cycle regulator CDKN1A (116899), and disrupts TGF-beta (TGFB1; 190180)-driven differentiation.
In 6 patients from 4 unrelated families with Grange syndrome (GRNG; 602531), characterized by progressive arterial occlusive disease with hypertension, bone fragility, and brachysyndactyly, with or without heart defects, Guo et al. (2017) identified homozygosity or compound heterozygosity for truncating mutations in the YY1AP1 gene (607860.0001-607860.0005). Noting that the heterozygous mother in 1 of the families (see 607860.0001) had refractory hypertension due to left renal artery stenosis, and that 1 of 282 patients with fibromuscular dysplasia (FMDA; 135580) was heterozygous for a frameshift mutation in the YY1AP1 gene, Guo et al. (2017) suggested that heterozygous loss-of-function YY1AP1 mutations might be associated with susceptibility to FMDA in the general population.
In 3 sibs with Grange syndrome, Rath et al. (2019) identified compound heterozygous loss-of-function splicing mutations in the YY1AP1 gene (607860.0006; 607860.0007). The mutations were identified by sequencing of near-splice regions and Sanger sequencing, after whole-exome sequencing failed to identify a candidate gene. All 3 sibs had internal carotid artery stenosis and hypertension; 2 had renal artery stenosis and 2 had syndactyly. Each asymptomatic parent carried one of the mutations, and an asymptomatic 12-year-old sib was heterozygous for the maternal mutation. The parents had no stenoocclusive lesions and the 12-year-old sib had as yet no vascular lesions. No functional studies were performed.
In 3 affected sibs (family DVD047) with Grange syndrome (GRNG; 602531), originally reported by Grange et al. (1998), Guo et al. (2017) identified compound heterozygosity for 2 nonsense mutations in the YY1AP1 gene: a c.724C-T transition (c.724C-T, NM_001198903.1) in exon 4, resulting in a gln242-to-ter (Q242X) substitution, and a c.2390T-A transversion in exon 10, resulting in a leu797-to-ter (L797X; 607860.0002) substitution. Their mother, who was heterozygous for the Q242X variant, had refractory hypertension, chronic renal insufficiency, and stenosis of the left renal artery. The mutation was not found in the ExAC database. Immunoblot analysis of proband fibroblasts showed no evidence of full-length or truncated protein.
For discussion of the c.2390T-A transversion (c.2390T-A, NM_001198903.1) in exon 10 of the YY1AP1 gene, resulting in a leu797-to-ter (L797X) substitution, that was found in compound heterozygous state in 3 sibs with Grange syndrome (GRNG; 602531) by Guo et al. (2017), see 607860.0001.
In a man (DVD093) with Grange syndrome (GRNG; 602531), who was originally reported by Weymann et al. (2001), Guo et al. (2017) identified homozygosity for a c.2401G-T transversion (c.2401G-T, NM_001198903.1) in exon 10 of the YY1AP1 gene, resulting in a glu801-to-ter (E801X) substitution. His parents were heterozygous for the mutation, which was not found in the ExAC database.
In a girl (DVD097) with Grange syndrome (GRNG; 602531), who was originally reported by Wallerstein et al. (2006), Guo et al. (2017) identified homozygosity for a 4-bp deletion (c.1903_1906delTCTG, NM_001198903.1) in exon 10 of the YY1AP1 gene, causing a frameshift predicted to result in a premature termination codon (Glu636ProfsTer13). Her parents were heterozygous for the mutation, which was not found in the ExAC database.
In a girl (DVD112) with features of Grange syndrome (GRNG; 602531), Guo et al. (2017) identified homozygosity for a c.664C-T transition (c.664C-T, NM_001198903.1) in exon 4 of the YY1AP1 gene, resulting in a gln222-to-ter (Q222X) substitution. The patient exhibited mild facial dysmorphism and brachydactyly of the hands and feet, but did not show bone fragility; in addition, CT angiography did not reveal any stenosis of the cerebral, renal, or other arteries, and echocardiography was normal.
In 3 sibs with Grange syndrome (GRNG; 602531), Rath et al. (2019) identified compound heterozygous mutations in the YY1AP1 gene: IVS5-4G-A (c.826-1G-A), inherited from the father, and IVS6+23T-G (c.977+23T-G, 607860.0007), inherited from the mother. The mutations were identified by sequencing of near-splice regions and Sanger sequencing, following failure of whole-exome sequencing to identify a candidate gene. A younger sib, aged 12 years, was heterozygous for the maternal mutation. The mutation in intron 5 was predicted to cause skipping of exon 6. The mutation in intron 6 was predicted to create a novel donor splice site in intron 6, resulting in a frameshift due to exonization of 22 intronic nucleotides (Ala333GlyfsTer10). The variants were classified as loss-of-function mutations and as pathogenic according to ACMG guidelines. The splice site defects were confirmed by RT-PCR in all 4 sibs and the carrier parents. The parents were asymptomatic and had no stenoocclusive lesions, and the 12-year-old sib had as yet no vascular lesions. The c.977+23T-G variant was not present in the gnomAD database, whereas the c.826-1G-A variant was present in 3 heterozygotes. Functional studies were not performed.
For discussion of the IVS6+23T-G mutation (c.997+23T-G) in the YY1AP1 gene that was found in compound heterozygous state in 3 sibs with Grange syndrome (GRNG; 602531) by Rath et al. (2019), see 607860.0006.
Grange, D. K., Balfour, I. C., Chen, S., Wood, E. G. Familial syndrome of progressive arterial occlusive disease consistent with fibromuscular dysplasia, hypertension, congenital cardiac defects, bone fragility, brachydactyly, and learning disabilities. Am. J. Med. Genet. 75: 469-480, 1998. [PubMed: 9489789] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980217)75:5<469::aid-ajmg4>3.0.co;2-i]
Guo, D., Duan, X.-Y., Regalado, E. S., Mellor-Crummey, L., Kwartler, C. S., Kim, D., Lieberman, K., de Vries, B. B. A., Pfundt, R., Schinzel, A., Kotzot, D., Shen, X., and 9 others. Loss-of-function mutations in YY1AP1 lead to Grange syndrome and a fibromuscular dysplasia-like vascular disease. Am. J. Hum. Genet. 100: 21-30, 2017. [PubMed: 27939641] [Full Text: https://doi.org/10.1016/j.ajhg.2016.11.008]
Kuryshev, V. Y., Vorobyov, E., Zink, D., Schmitz, J., Rozhdestvensky, T. S., Munstermann, E., Ernst, U., Wellenreuther, R., Moosmayer, P., Bechtel, S., Schupp, I., Horst, J., Korn, B., Poustka, A., Wiemann, S. An anthropoid-specific segmental duplication on human chromosome 1q22. Genomics 88: 143-151, 2006. [PubMed: 16545939] [Full Text: https://doi.org/10.1016/j.ygeno.2006.02.002]
Rath, M., Spiegler, S., Strom, T. M., Trenkler, J., Kroisel, P. M., Felbor, U. Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing. Am. J. Med. Genet. 179A: 295-299, 2019. [PubMed: 30556293] [Full Text: https://doi.org/10.1002/ajmg.a.60700]
Wallerstein, R., Augustyn, A. M., Wallerstein, D., Elton, L., Tejeiro, B., Johnson, V., Lieberman, K. A new case of Grange syndrome without cardiac findings. Am. J. Med. Genet. 140A: 1316-1320, 2006. [PubMed: 16691574] [Full Text: https://doi.org/10.1002/ajmg.a.31125]
Wang, Z.-X., Wang, H.-Y., Wu, M.-C. Identification and characterization of a novel human hepatocellular carcinoma-associated gene. Brit. J. Cancer 85: 1162-1167, 2001. [PubMed: 11710830] [Full Text: https://doi.org/10.1054/bjoc.2001.2059]
Weymann, S., Yonekawa, Y., Khan, N., Martin, E., Heppner, F. L., Schinzel, A., Kotzot, D. Severe arterial occlusive disorder and brachysyndactyly in a boy: a further case of Grange syndrome? Am. J. Med. Genet. 99: 190-195, 2001. [PubMed: 11241488] [Full Text: https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1138>3.0.co;2-r]