Johanson–Blizzard syndrome (JBS) is a rare, sometimes fatal autosomal recessive multisystem congenital disorder featuring abnormal development of the pancreas, nose and scalp, with intellectual disability, hearing loss and growth failure.

[2] The disorder is especially noted for causing profound developmental errors and exocrine dysfunction of the pancreas, and it is considered to be an inherited pancreatic disease.

[1] The islets of Langerhans are ducts in the pancreas where endocrine activity such as the release of hormones glucagon, somatostatin and insulin takes place.

[1][2][7] Both hypoplasia and aplasia (partial or complete absence) of structural cartilage and tissue in this area of the nose, along with the underlying alae nasi muscle, are prevailing features of the disorder.

[7][15] Intellectual disability ranging from mild to severe is present in the majority of Johanson–Blizzard syndrome patients, and is related to the deleterious nature of the known mutagen responsible for the disorder and its effects on the developing central nervous system.

[12][16] Findings with the inner ear in Johanson–Blizzard syndrome give explanation to the presence of bilateral sensorineural hearing loss in most patients affected by the disorder.

[7][9][17] Congenital deformations of the temporal bone and associated adverse anatomical effects on innervation and development of the inner ear also contribute to this type of hearing loss.

These include: ectodermal mid-line scalp defects with sparse, oddly-patterned hair growth;[2][9] aplasia cutis (underdeveloped, very thin skin) over the head,[19] an enlarged fontanelle ("soft spot" on the head of young infants),[14] microcephaly (undersized skull),[19] prominent forehead,[14] absence of eyebrows and eyelashes,[14] mongoloid eye shape,[17] nasolacrimo- cutaneous fistulae (this refers to the formation of an abnormal secondary passageway from either the tear duct or lacrimal sac to the facial skin surface, possibly discharging fluid),[9] flattened ears,[14] micrognathism of the maxilla and mandible (underdevelopment of the upper and lower jaw, respectively), with the maxilla more prominently affected in some cases;[14][20][21] congenital clefting of bones surrounding the optical orbit (eye socket), such as the frontal and lacrimal bone;[20] and maldeveloped deciduous teeth ("baby teeth"), with an absence of permanent teeth.

[9][14] Additional congenital anomalies, effects on other organs, and less common features of JBS have included: imperforate anus (occlusion of the anus),[22] vesicoureteral reflux (reversal of the flow of urine, from the bladder back into the ureters, toward the kidneys);[14] duplex of the uterus and vagina in female infants,[7] neonatal cholestasis of the liver, with cirrhosis and portal hypertension (high blood pressure in the hepatic portal vein);[22] dilated cardiomyopathy,[23] dextrocardia (congenital displacement of the heart to the right side of the chest),[1] atrial and ventricular septal defect;[1] low birth-weight,[24] failure to thrive,[24] hypotonia (decreased muscle tone);[19] sacral hiatus (a structural deficiency of the sacral vertebrae),[24] congenital cataracts,[24] and cafe-au-lait spots.

[26] The direct connection between UBR1 mutations altering the protein degradation system and specific Johanson–Blizzard syndrome 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.

[27] 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.

[25] 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.

[29] The last homozygous mutation turns guanine to adenine in intron 12 by skipping exon 13 through a frameshift and causing premature termination.

[1] Impairment of the ubiquitin-proteasome system directly related to insufficient activity of ubiquitin ligase has been established as the cause of both congenital and progressive inflammatory damage, fatty tissue replacement, connective tissue proliferation and errors in innervation of the acini and islets, correlating to failures of normal apoptotic destruction of damaged cells and constitutive malpresence of proteins.

Variability of the phenotype, associated with residual ubiquitin ligase activity in some patients, has also been attributed to hypomorphic mutations occasionally found in either of the carrier parents.

[40][27] Saccharomyces cerevisiae also contains regions essential for recognition of the N-end rule substrates by UBR1 protein, as well as rabbits for through reticulocyte tryptic peptides after purification to E3α.