<unk>  has an autosomal recessive pattern of inheritance.<unk>  has an autosomal recessive pattern of inheritance resulting from loss of function (usually deleterious as nonsense, frameshift, or splice site) mutations in the Ubiquitin-Protein Ligase E3 Component N- Recognin gene (UBR1), which encodes for a specific ubiquitin ligase enzyme. This means the defective UBR1 gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the<unk> . The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.<unk>  results from one or multiple mutations in UBR1, specifically at a fixed chromosomal position known as locus 15q15.2 or human chromosome 15, q-arm region 1, band 5, sub-band 2. This gene spans around 161kb (161,000 base pairs) in length and contains 47 exons expressed as mRNA. In comparison, mouse 120kb UBR1 is in the middle of chromosome 2 and shows homology of synteny (co-localized loci in same chromosome) with its human counterpart through its 50 exons. The protein has also been weighed in at 200-kD in mice compared to 225-kD in Saccharomyces cerevisiae. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway. This pathway consists of a conserved proteolytic system of proteins that destabilize N-terminal residues, meaning UBR1 codes for proteins with degron parts that send degradation signals to the cell, inducing metabolic instability. This specific signal is called N-degron, and its causal set of peptides yields the N-end rule, which relates the protein's in vivo half-life to the identity of its N-terminal residue through a ubiquitin system (N-end rule pathway). The N-recognin, also known as E3, binds to the destabilizing N-terminal residue of a substrate protein to form a substrate-linked miltiubiquitin chain. The direct connection between UBR1 mutations altering the protein degradation system and specific<unk>  clinical anomalies (symptoms of diagnosis) is still undetermined as origin of possible mutagenic genetic variations varies from just the father alleles to both alleles; and single or multi-exon deletions/duplications in which all 47 UBR1 exons must be taken into account when performing Sanger sequencing and Multiplex ligation-dependent probe amplification (MLPA), meaning there is no obvious candidate gene. However, most certain UBR1 mutations predict premature translational stop codons, with two missense mutations altering residues highly conserved among different species. One of these missense mutations affects a conserved motif important for UBR1 substrate-binding by converting histidine at location 136 to arginine accompanied by intervening sequence. Bidirectional analysis of all 47 exons (including ~20bp flanking intronic regions) reveals homozygous mutation in exon 19, where threonine nucleotide substitutes cysteine, resulting in a missensed serine residue between peptide locations 698 and 702 completely conserved throughout vertebrate UBR1 (even UBR2) protein. Another cysteine to threonine mutation, but homozygous nonsense in nature, has also been confirmed in<unk>  patients with no functional UBR1 protein, but mild symptoms are also common in missense mutations in at least one of the two UBR1 copies with possible residual activity of gene product. 2 Heterozygous mutations from nonconsanguineous parents arise from adenine to guanine conversion at nucleotide 407 resulting in a histidine 136 substitution to arginine at splice donor site. Next non-consanguineous homozygous nonsense mutation happens at glutamine 513 becoming a stop codon by a cytosine to thymine conversion caused by a cytosine to thymine transition at nucleotide 1537 in exon 13. Continuing homozygous mutations, one converts guanine to adenine, in intron 26 resulting in residual normal protein production. The last homozygous mutation turns guanine to adenine in intron 12 by skipping exon 13 through a frameshift and causing premature termination. Maternally inherited heterozygous nonsense mutation of cysteine to adenine resulting in a tyrosine has also been classified at residue 1508. Another heterozygous missense mutation on leucine linked to an arganine at exon 44 is considered pathogenic because leucine at residue 1597 is highly conserved among different species. Lastly, a splice site mutation has been identified intervening sequence changing thymine for cytosine at nucleotide 20.
Johanson–Blizzard syndrome
Cystic fibrosis
Gómez–López-Hernández syndrome
Secretan's syndrome
Fitz-Hugh–Curtis syndrome
Naegeli–Franceschetti–Jadassohn syndrome
Lucey–Driscoll syndrome
Zollinger–Ellison syndrome