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Genetics[ edit]
Johanson-Blizzard syndrome has an autosomal recessive pattern of inheritance resulting from loss-of-function (usually deleterious as nonsense,frameshift, or splice-site) mutations in UBR1 gene. JBS is inherited in an Autosomal Recessive manner. This means the defective 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 disorder. 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.

UBR 1
Genetic defect causing JBS results from mutations in UBR 1 gene on chromosome 15q15-21, which 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 destabilizing N-terminal residues, but pathophysiological link between altering protein degradation and JBS clinical anoimalies is still undetermined. This might be due to the possibility ofsingle or multi-exon deletions/duplications accounting for a substantial proportion of JBS-associated UBR1 mutations. Complexity arises as copy number of all 47 UBR1 exons must be taken into account when performing analytical methods such as Sanger sequencing and multiplex-dependent probe amplification (MLPA). Bidirectional analysis of all 47 exons (including ~20bp flanking intronic regions) reveals homozygous mutation in exon 19, where c.2089C>T substitution predicts missense in p.S700P affecting residue 100% conserved throughout vertebrate protein (as well as UBR2) though non-polymorphic. Thus evidently, p.S700P is one of the mutations causing JBS. Homozygous nonsense mutation in UBR1 (c.3682C>T; p.Q1228X) has also been confirmed in JBS patients with no functional 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. Maternal inherited heterozygous nonsense mutation of c.4524T>A, p.Tyr1508 has also been classified in JBS but paired with exons 45,46, and 47 deletion assumed from paternal allele. Missense mutation p.Leu1597Arg (c.4790T>G) in exon 44 might be meaningful as leucine residue at position 1597 is highly conserved among different species, found alongside deletion of exon 33 in second allele. However, heterozygous missense mutation (c.1688C>A, p. Ala563Asp) was accompanied by no mutation on second allele, but instead its reduced expression (or increased degradation), meaning a possible mutation in promoter or intronic region with larger genomic rearrangement could erradicate missense mutation in UBR1. There might also be no homozygosity at UBR1 locus for no reduction in expression, concluding that no point mutations are detectable in either one or bothe alleles (n=3) representing nine total accopanying JBS phenotype. Because of this, deletion/duplication analysis is crucial if point mutation screening does not reveal mutation in one or both alleles.