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UBIQUITIN PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 7; UBR7

UBIQUITIN PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 7; UBR7

HGNC Approved Gene Symbol: UBR7Cytogenetic location: 14q32.12 Genomic coordinates (GRCh38): 14:93,207,255-93,229,214 (from NCBI)▼ DescriptionThe UBR7 gene en...

HGNC Approved Gene Symbol: UBR7

Cytogenetic location: 14q32.12 Genomic coordinates (GRCh38): 14:93,207,255-93,229,214 (from NCBI)

▼ Description
The UBR7 gene encodes a putative E3 ligase that acts as an N-recognin for the degradation of substrates with destabilizing residues. The N-end rule pathway of protein degradation uses destabilizing N-terminal residues that function as essential components of a degradation signal, or N-degron, to target the protein for ubiquitination and proteasomal degradation. N-degrons are found in short-lived proteins or can be created by specific N-terminal modifications of otherwise stable proteins. UBR7 is predicted to be one of several ubiquitin E3 ligases that attach ubiquitin chains to proteins containing N-degrons (review by Tasaki and Kwon, 2007).

▼ Cloning and Expression
In their review, Tasaki and Kwon (2007) stated that mammalian UBR7 is a 50-kD protein with an N-terminal UBR domain and a C-terminal plant homeodomain (PH) finger.

▼ Mapping
Hartz (2011) mapped the UBR7 gene to chromosome 14q32.12 based on an alignment of the UBR7 sequence (GenBank AK001345) with the genomic sequence (GRCh37).

▼ Gene Function
Using proximity labeling and proteomic analysis, Zhang et al. (2019) identified Ubr7 as a regulator of immunity mediated by N, a nucleotide-binding leucine-rich repeat (NLR) immune receptor, in the model plant Nicotiana benthamiana. Ubr7 of N. benthamiana interacted with the TIR domain of N protein and modulated its stability, thereby negatively regulating N-mediated defense against Tobacco mosaic virus (TMV). The TMV effector p50 enhanced the stability of N and induction of resistance to TMV by disrupting the interaction between Ubr7 and N protein.

▼ Molecular Genetics
In 7 patients from 6 unrelated families with Li-Campeau syndrome (LICAS; 619189), Li et al. (2021) identified homozygous or compound heterozygous mutations in the UBR7 gene (see, e.g., 613816.0001-613816.0006). The mutations, which were found by exome or genome sequencing, segregated with the disorder in the family. The mutations included 2 frameshifts, 1 nonsense, 2 splice site, 1 missense, and an intragenic deletion. All but 1 were absent from the gnomAD database (v2.1.1); the exception was a frameshift found in only 1 allele in gnomAD. All mutations were predicted to result in a loss of function, although specific functional studies were not performed. Cells derived from 3 patients showed loss of the UBR7 protein. Knockdown of the orthologous gene in C. elegans resulted in developmental defects and was associated with abnormal NOTCH signaling in germline stem cells that likely influenced development and embryo formation.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 LI-CAMPEAU SYNDROME
UBR7, GLU13TER
In a 9-year-old boy (P1) with Li-Campeau syndrome (LICAS; 619189), Li et al. (2021) identified compound heterozygous loss-of-function mutations in the UBR7 gene: a c.37G-T transversion (c.37G-T, NM_175748.4), resulting in a glu13-to-ter (E13X) substitution, and a 2-bp duplication (c.564_565dup; 613816.0002), predicted to result in a frameshift and premature termination (Cys189PhefsTer14). The mutations, which were found by exome sequencing, segregated with the disorder in the family. E13X was not present in the gnomAD database (v2.1.1), whereas the frameshift was found in 1 of 209,572 alleles. Patient-derived lymphoblastoid cells showed loss of the UBR7 protein.

.0002 LI-CAMPEAU SYNDROME
UBR7, 2-BP DUP, NT564
For discussion of the 2-bp duplication (c.564_565dup, NM_175748.4) in the UBR7 gene, predicted to result in a frameshift and premature termination (Cys189PhefsTer14), that was found in compound heterozygous state in a patient with Li-Campeau syndrome (LICAS; 619189) by Li et al. (2021), see 613816.0001. (In the article by Li et al. (2021), this mutation is also listed as c.563_564insTT, resulting in the same frameshift.)

.0003 LI-CAMPEAU SYNDROME
UBR7, IVS6AS, A-G, -2
In a 3.9-year-old boy (P3) with Li-Campeau syndrome (LICAS; 619189), who was born to nonconsanguineous parents, Li et al. (2021) identified compound heterozygous loss-of-function mutations in the UBR7 gene: an A-to-G transition at the splice acceptor site of exon 6 (c.496-2A-G, NM_175748.4), demonstrated to result in a splice site alteration and the skipping of exon 6, and an intragenic deletion encompassing exons 1-10 (613816.0004), sparing the last exon. The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. They were not present in the gnomAD database (v2.1.1). Analysis of patient fibroblasts showed loss of the UBR7 protein, indicating that the splice site mutation was subject to nonsense-mediated mRNA decay.

.0004 LI-CAMPEAU SYNDROME
UBR7, EX1-10DEL
For discussion of the intragenic deletion encompassing exons 1-10 (chr14.93,660,388_93,690,906del, GRCh37) of the UBR7 gene that was found in compound heterozygous state in a patient with Li-Campeau syndrome (LICAS; 619189) by Li et al. (2021), see 613816.0003.

.0005 LI-CAMPEAU SYNDROME
UBR7, 1-BP DEL, 618T
In 2 unrelated boys (P4 and P5), each born of consanguineous parents of Saudi Arabian origin, with Li-Campeau syndrome (LICAS; 619189), Li et al. (2021) identified a homozygous 1-bp deletion (c.618delT, NM_175748.4) in the UBR7 gene, predicted to result in a frameshift and premature termination (Glu207ArgfsTer12). The mutation, which was found by genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database (v2.1.1). Fibroblasts derived from P5 showed absence of the UBR7 protein, consistent with a loss of function. Functional studies of the variant were not performed.

.0006 LI-CAMPEAU SYNDROME
UBR7, c.1186-1G-C
In 2 sibs (P6 and P7), born of consanguineous parents, with Li-Campeau syndrome (LICAS; 619189), Li et al. (2021) identified a homozygous G-to-C transversion in the UBR7 gene (c.1186-1G-C, NM_175748.4), predicted to result in a splicing alteration. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database (v2.1.1). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.

Tags: 14q32.12

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