Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis.

Abstract

BACKGROUND:

Johanson-Blizzard syndrome (JBS, MIM #243800) is a very rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, nasal wing hypoplasia, hypodontia, and other abnormalities. JBS is caused by mutations of the UBR1 gene (MIM *605981), encoding a ubiquitin ligase of the N-end rule pathway.

METHODS:

Molecular findings in a total of 65 unrelated patients with a clinical diagnosis of JBS who were previously screened for UBR1 mutations by Sanger sequencing were reviewed and cases lacking a disease-causing UBR1 mutation on either one or both alleles were included in this study. In order to discover mutations that are not detectable by Sanger sequencing, we designed a probe set for multiplex ligation-dependent probe amplification (MLPA) analysis of the UBR1 gene and analyzed the copy number status of all 47 UBR1 exons.

RESULTS:

Our previous studies using Sanger sequencing could detect mutations in 93.1% of 130 disease-associated UBR1 alleles. Six patients with a highly suggestive clinical diagnosis of JBS and unsolved genotype were included in this study. MLPA analysis detected six alleles harboring exon deletions/duplications, thereby raising the mutation detection rate in the entire cohort to 97.7% (127/130 alleles).

CONCLUSION:

We conclude that single or multi-exon deletions or duplications account for a substantial proportion of JBS-associated UBR1 mutations.

• Authors: Maja Sukalo, Eva Schäflein, Ina Schanze, David B Everman, Nima Rezaei, Jesús Argente, Isabel Lorda-Sanchez, Charu Deshpande, Tsutomu Takahashi, Alexander Kleger, Martin Zenker
• Journal: Molecular genetics & genomic medicine (Mol Genet Genomic Med) Vol. 5 Issue 6 Pg. 774-780 (11 2017) ISSN: 2324-9269 [Electronic] United States
• PMID: 29178640 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Chemical References

• DNA
• UBR1 protein, human
• Ubiquitin-Protein Ligases

Topics

• Adult
• Alleles
• Anus, Imperforate (diagnosis, genetics)
• Base Sequence
• Child
• Child, Preschool
• DNA (chemistry, isolation & purification, metabolism)
• DNA Mutational Analysis
• Ectodermal Dysplasia (diagnosis, genetics)
• Exons
• Female
• Gene Deletion
• Gene Duplication
• Genotype
• Growth Disorders (diagnosis, genetics)
• Hearing Loss, Sensorineural (diagnosis, genetics)
• Humans
• Hypothyroidism (diagnosis, genetics)
• Intellectual Disability (diagnosis, genetics)
• Male
• Multiplex Polymerase Chain Reaction
• Nose (abnormalities)
• Pancreatic Diseases (diagnosis, genetics)
• Phenotype
• Ubiquitin-Protein Ligases (genetics)