Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing.

Abstract

Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 because association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that TRIM32/ASTN2 inactivation could be associated with cognitive impairment.

• Authors: Juliette Nectoux, Rafael de Cid, Sylvain Baulande, France Leturcq, Jon Andoni Urtizberea, Isabelle Penisson-Besnier, Aleksandra Nadaj-Pakleza, Carinne Roudaut, Audrey Criqui, Lucie Orhant, Delphine Peyroulan, Raba Ben Yaou, Isabelle Nelson, Anna Maria Cobo, Marie-Christine Arné-Bes, Emmanuelle Uro-Coste, Patrick Nitschke, Mireille Claustres, Gisèle Bonne, Nicolas Lévy, Jamel Chelly, Isabelle Richard, Mireille Cossée
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 23 Issue 7 Pg. 929-34 (Jul 2015) ISSN: 1476-5438 [Electronic] England
• PMID: 25351777 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Transcription Factors
• Tripartite Motif Proteins
• TRIM32 protein, human
• Ubiquitin-Protein Ligases

Topics

• Adult
• Base Sequence
• Comparative Genomic Hybridization (methods)
• DNA Mutational Analysis (methods)
• Family Health
• Female
• Gene Deletion
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• Male
• Muscular Dystrophies, Limb-Girdle (genetics, pathology)
• Pedigree
• Transcription Factors (genetics)
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases