Alternative titles; symbols
HGNC Approved Gene Symbol: YIPF5
Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38): 5:144,158,162-144,170,659 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.3 | Microcephaly, epilepsy, and diabetes syndrome 2 | 619278 | Autosomal recessive | 3 |
YIPF5 is essential for innate immunity to DNA viruses by facilitating coat protein complex II (COPII; see 610511)-dependent trafficking of STING (STING1; 612374) (Ran et al., 2019).
By RT-PCR and 3-prime RACE of a human coronary smooth muscle cell RNA, Stolle et al. (2005) cloned YIPF5, which they called SMAP5. By searching EST databases and by exon-specific PCR, they identified 9 splice variants. The most common transcript encodes a deduced 257- amino acid protein with 4 or 5 transmembrane domains forming a characteristic Rab GTPase-interacting factor domain. Northern blot analysis detected a major 2-kb transcript expressed at highest levels in liver, heart, skeletal muscle, kidney, and small intestine with low to no expression in other tissues analyzed. Heart and skeletal muscle expressed an additional 7-kb transcript. RT-PCR analysis detected highest expression in coronary smooth muscle cells, followed by duodenum, heart, ileum, jejunum, pancreas, prostate, retina, small intestine, uterus, fibroblasts, and colon and lung tumor. SMAP5 colocalized with a cis-Golgi marker in transfected HeLa cells. By PCR of a human testis cDNA library, Jin et al. (2005) independently cloned YIPF5, which they called YIP1A.
Using qPCR in human tissues, De Franco et al. (2020) observed that YIPF5 is ubiquitously expressed, with abundant expression in pancreatic tissue, islets, beta cells, and brain. In situ hybridization in human fetal brain samples from 12 to 21 gestational weeks revealed significant broad expression of YIPF5 in the developing cortex at all stages examined, but most strikingly at 12 weeks. Expression was found in both progenitor (ventricular zone) and neuronal (intermediate zone and cortical plate) compartments. Some selective expression could also be detected in the choroid plexus within the cerebral ventricles.
Stolle et al. (2005) determined that the YIPF5 gene contains 6 coding exons and spans about 12.5 kb. The promoter region is GC-rich with 10 putative SP1 (189906)-binding sites but lacks a TATA box.
By genomic sequence analysis, Stolle et al. (2005) mapped the YIPF5 gene to chromosome 5q32.
Stolle et al. (2005) showed that YIPF5 was significantly induced by TGFB1 (190180) in coronary smooth muscle cells but not in fibroblasts.
Using reciprocal yeast 2-hybrid analysis and coimmunoprecipitation assays, Jin et al. (2005) showed that YIP1A and YIF1A (611484) interact directly. Both proteins localized to the Golgi apparatus in transfected human embryonic kidney cells, and the Golgi localization of YIF1A depended upon the transmembrane domain of YIP1A.
Ran et al. (2019) found that YIPF5 positively regulated innate immune responses to DNA viruses in human and mouse immortalized cell lines and primary cells. YIPF5 specifically regulated viral infection-induced expression of type I IFNs and downstream IFN-stimulated genes. YIPF5 was also important for cellular antiviral responses against DNA but not RNA viruses. Immunoprecipitation analysis and confocal microscopy revealed that YIPF5 interacted and colocalized with STING in DNA virus-triggered pathways. The interaction was facilitated by the C-terminal transmembrane domains of YIPF5 and the fourth transmembrane domain of STING. YIPF5 mediated STING trafficking from ER to Golgi by recruiting it to COPII-coated vesicles, which were essential for the STING-mediated innate immune response to intracellular DNA.
Using siRNA silencing, De Franco et al. (2020) knocked out YIPF5 in stem cell-derived pancreatic beta cells and observed proinsulin retention in the endoplasmic reticulum (ER) as well as marked ER stress and beta cell failure. Transmission electron microscopy showed pronounced ER distension in the beta cells, resulting from proinsulin accumulation in the ER. However, the authors noted that the ER in YIPF5-knockout pancreatic alpha cells was not affected, suggesting that YIPF5 is specifically essential for proinsulin trafficking from the ER in beta cells.
In 6 affected individuals from 5 consanguineous families with microcephaly, epilepsy, and diabetes syndrome-2 (MEDS2; 619278), De Franco et al. (2020) identified homozygosity for mutations in the YIPF5 gene (611483.0001-611483.0005). The unaffected consanguineous parents in all families were heterozygous for the mutations, none of which was found in the gnomAD database. Functional analysis demonstrated that YIPF5 deficiency affects beta-cell function by enhancing ER stress and sensitizing human beta cells to ER stress-induced apoptosis.
In a 5-year-old Turkish boy (patient I) with severe microcephaly, generalized tonic-clonic seizures that began at 2 months of age, and diabetes that was diagnosed at age 9 weeks (MEDS2; 619278), De Franco et al. (2020) identified homozygosity for a c.542C-T transition (c.542C-T, NM_001024947.3) in the YIPF5 gene, resulting in an ala181-to-val (A181V) substitution at a highly conserved residue within the third transmembrane domain. His first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database.
In an Indian boy (patient II) who died at 1.3 years of age with severe microcephaly, generalized tonic-clonic seizures that began at 4 months of age, and diabetes that was diagnosed at age 15 weeks (MEDS2; 619278), De Franco et al. (2020) identified homozygosity for an in-frame 3-bp deletion (c.317_319del, NM_001024947.3) in the YIPF5 gene, resulting in deletion of a highly conserved residue (lys106del, K106del) within the cytoplasmic domain. His first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database. The proband had 4 affected sibs who also died in infancy; DNA from the sibs was not available for analysis.
In 2 Turkish sisters, ages 21 years (patient IIIa) and 15 years (patient IIIb), who had severe microcephaly, generalized tonic-clonic seizures, and diabetes that was diagnosed at age 15 months and 8.5 months, respectively (MEDS2; 619278), De Franco et al. (2020) identified homozygosity for a c.293T-G transversion (c.293T-G, NM_001024947.3) in the YIPF5 gene, resulting in an ile98-to-ser (I98S) substitution at a highly conserved residue within the cytoplasmic domain. Their first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database. The authors studied stem cell-derived beta cells with the I98S mutation and concluded that the variant does not compromise differentiation and function of beta cells, but affects cell survival by sensitizing them to ER stress-induced apoptosis.
In a 5.5-year-old Turkish girl (patient IV) with severe microcephaly, generalized tonic-clonic seizures that began at 1 month of age, and diabetes that was diagnosed at age 4 weeks (MEDS2; 619278), De Franco et al. (2020) identified homozygosity for a c.652T-A transversion (c.652T-A, NM_001024947.3) in the YIPF5 gene, resulting in a trp218-to-arg (W218R) substitution at a highly conserved residue within the fourth transmembrane domain. Her second-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database.
In a 6-month-old Indian boy (patient V) with severe microcephaly, generalized tonic-clonic seizures that began at 3 months of age, and diabetes that was diagnosed at age 23 weeks (MEDS2; 619278), De Franco et al. (2020) identified homozygosity for a c.290G-T transversion (c.290G-T, NM_001024947.3) in the YIPF5 gene, resulting in a gly97-to-val (G97V) substitution at a highly conserved residue within the cytoplasmic domain. His first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database.
De Franco, E., Lytrivi, M., Ibrahim, H., Montaser, H., Wakeling, M. N., Fantuzzi, F., Patel, K., Demarez, C., Cai, Y., Igoillo-Esteve, M., Cosentino, C., Lithovius, V., and 27 others. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. J. Clin. Invest. 130: 6338-6353, 2020. [PubMed: 33164986] [Full Text: https://doi.org/10.1172/JCI141455]
Jin, C., Zhang, Y., Zhu, H., Ahmed, K., Fu, C., Yao, X. Human Yip1A specifies the localization of Yif1 to the Golgi apparatus. Biochem. Biophys. Res. Commun. 334: 16-22, 2005. [PubMed: 15990086] [Full Text: https://doi.org/10.1016/j.bbrc.2005.06.051]
Ran, Y., Xiong, M., Xu, Z., Luo, W., Wang, S., Wang, Y.-Y. YIPF5 is essential for innate immunity to DNA virus and facilitates COPII-dependent STING trafficking. J. Immun. 203: 1560-1570, 2019. Note: Erratum: J. Immun. 208: 1310 only, 2022. [PubMed: 31391232] [Full Text: https://doi.org/10.4049/jimmunol.1900387]
Stolle, K., Schnoor, M., Fuellen, G., Spitzer, M., Engel, T., Spener, F., Cullen, P., Lorkowski, S. Cloning, cellular localization, genomic organization, and tissue-specific expression of the TGF-beta-1-inducible SMAP-5 gene. Gene 351: 119-130, 2005. [PubMed: 15922870] [Full Text: https://doi.org/10.1016/j.gene.2005.03.012]