Novel UBR1 gene mutation in a patient with typical phenotype of Johanson–Blizzard syndrome

Abstract

Johanson-Blizzard syndrome is a rare autosomal recessive disorder, characterized by exocrine pancreatic deficiency and a wide range of other abnormalities. We present here an infant with failure to thrive, exocrine pancreatic deficiency, short stature and developmental delay, cutis aplasia on the scalp, aplasia of alae nasi, hypospadias, hypothyroidism, myxomatous mitral valve, and patent ductus arteriosus. Molecular studies revealed a novel homozygous nonsense mutation in exon 38 of the UBR1 gene, which confirmed the diagnosis of Johanson-Blizzard syndrome. It should be acknowledged that the combination of exocrine pancreatic insufficiency and nasal wing hypo-aplasia is pathognomonic for this syndrome. Prompt diagnosis and exact monitoring of the patients with JBS are required to avoid further complications.

Case Report Johanson-Blizzard syndrome: a report of gender-discordant twins with a novel UBR1 mutation

“…A severe presentation of JBS usually involves deleterious (nonsense, frameshift, or splice-site) mutations in the UBR1 gene that are thought to completely abolish the expression of a functional protein product (Zenker et al, 2005;Alkhouri et al, 2008;Fallahi et al, 2011;Hwang et al, 2011). However, milder involvement of JBS is associated with missense mutations in at least 1 of the 2 copies of UBR1, in which residual activity of the product of this gene would prevent a more severe clinical manifestation (Hwang et al, 2011).…”

“…The male twin presented typical clinical features of JBS (listed in order of prevalence in patients with JBS): pancreatic insufficiency (98%), nasal alae hypoplasia (98%), dental hypoplasia/agenesis (96%), short stature (84%), scalp defects (72%), deafness (69%), and mental retardation (69%) (Al-Dosari et al, 2008;Alkhouri et al, 2008;Elting et al, 2008;Almashraki et al, 2011;Fallahi et al, 2011;Hwang et al, 2011).…”

“…Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disorder resulting from loss-of-function mutations in the UBR1 gene, which is located on chromosome 15q15-21 (Varshavsky, 1996;Kwon et al, 1998;Kwak et al, 2004;Zenker et al, 2005;Almashraki et al, 2011;Fallahi et al, 2011;Rezaei et al, 2011). Although JBS can be easily recognized by its unique clinical presentation (including exocrine pancreatic insufficiency, hypoplasia/aplasia of the alae nasi, congenital scalp defects, sensorineural hearing loss, growth retardation, psychomotor retardation, and anal and genitourinary anomalies), the detailed pathophysiological connection between the altered product of the UBR1 gene and the clinical anomalies observed in JBS remains to be determined.…”

Clinical utility gene card for: Johanson–Blizzard syndrome

“…Fifty-nine different mutations are known (including published mutations [1][2][3][4][5][6][7][8] and unpublished mutations identified in our lab). These include nonsense mutations (15), splice site mutations (14), small deletions and duplications/insertions causing frameshift (9), small inframe deletions (3) and missense mutations (18).…”

Role of the ubiquitin–proteasome system in nervous system function and disease: using C. elegans as a dissecting tool

“…Intriguingly, mutations in UBR1, the RING finger E3 that cooperates with UBE2A/HR6A in N-end rule targeting [128,134], have been associated with the Johanson-Blizzard syndrome which includes intellectual disability as a key feature [135][136][137][138]. Patients with this genetic syndrome suffer from congenital exocrine pancreatic insufficiency, growth retardation, hypothyroidism, hearing loss, and multiple malformations, such as nasal wing aplasia, oligodontia, cardiac anomalies, scalp defects, and imperforate anus, and frequently developmental delay/intellectual disability.…”