Structural organization and developmental expression pattern of the mouse WD-repeat gene DMR-N9 immediately upstream of the myotonic dystrophy locus

Gert Jansen, Dietmar B̈ächner, Marga Coerwinkel, Nicole Wormskamp, Horst Hameister, Bé Wieringa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

55 Citations (Scopus)

Abstract

The diverse biological consequences of size-expansion of the unstable (CTG)n repeat in the myotonic dystrophy protein kinase (DM-PK) gene at chromosome region 19q13.3, are still poorly understood. Abnormal (CTG)n length may aftect either DM-PK mRNA fate or function, or alternatively, compromise gene transcription by distortion of chromatin configuration. In the latter model involvement of neighbouring genes in DM upon extreme expansion of the repeat cannot be discarded as a possibility and should be studied further. Here we report on the elucidation of the complete genomic structure and expression pattern of the mouse DMR-N9 gene (called 59 gene in humans), which is at 1.1 kbp upstream of the DM-PK gene. This gene contains five exons spanning 7 kbp and codes for a protein of 650 amino acids. Two regions of the predicted protein show significant homology to WD repeats, highly conserved amino acid sequences found in a family of proteins engaged in signal transduction or cell regulatory functions. The start site of transcription has been determined and we have identified putative transcription factor binding sequences in a 400 bp putative promoter area Immediately upstream of the transcribed unit. Northern blotting analysis and RNA In situ hybridization revealed ubiquitous low expression in all tissues of the mouse embryo and enhanced expression in adult brain and testis. The onset of transcription is phased early in mouse embryogenesis, before or at day 9.5 of gestation. From day 14.5 onwards DMR-N9 mRNAs were detected in all neural tissues, especially in the telencephalon and mesencephalon. Later, mRNA presence is evident in distinct tubules of the mature testis, restricted to secondary spermatocytes of stages VIII to XII of the spermatogenic proliferation cycle. We conclude that the DMR-N9 gene is a candidate for being involved in the manifestation of mental and testicular symptoms in severe cases of DM.

Original languageEnglish
Pages (from-to)843-852
Number of pages10
JournalHuman Molecular Genetics
Volume4
Issue number5
DOIs
Publication statusPublished - May 1995
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to Dr W.Hendriks for performing computer analyses. This work was supported by grants to B.W. by the American Muscular Dystrophy Association (MDA), the Dutch Beatrixfonds and NWO (grant 900-501-140) and the Association Francaise contre les Myopathies (AFM) H.H. and D.B. were supported by grants of the Deutsche Forschungsgemeinschaft.

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