A novel Wiskott-Aldrich syndrome protein (WASP) complex mutation identified in a WAS patient results in an aberrant product at the C-terminus from two transcripts with unusual polyA signals

Abstract

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia and eczema. A broad spectrum of mutations in the WASP gene has been identified as causing the disease. In the present paper, we report on a patient affected by WAS with a novel complex mutation, characterized by a small 9 bp deletion followed by an inversion of 151 bp and a gross deletion of 4.3 kb within the Xp11.23 region. The small deletion and the inverted fragment are found in intron 11. The large deletion initiates downstream of exon 11 of the WASP gene, including exon 12, and a genomic region upstream of the promoter of the contiguous SUV39H1 gene. Expression studies of the mRNA of the patient's sample showed the presence of two aberrant transcripts that code for a protein of 519 amino acids. We demonstrate that these two transcripts differ in the 3¢ UTR region, and result from the use of two alternative polyadenylation signals. The severe phenotype of the patient correlates with the presence of an aberrant protein.

The lavender plumage colour in Japanese quail is associated with a complex mutation in the region of MLPH that is related to differences in growth, feed consumption and body temperature

“…In Human, complex chromosome rearrangements have been observed in cancer cells, and some are even characteristic of specific cancers [25], and other genetic diseases. For example, the Wiskott-Aldrich syndrome results from a complex mutation due to two deletions and one inversion in a 4.5-kb region [26]. In that example, the three chromosomal events were contiguous, but it has not been confirmed that they were overlapping, and the family study revealed that the complex mutation appeared in a single step.…”

Detection of novel 3' untranslated region extensions with 3' expression microarrays

“…Mice carrying this polymorphism have macrophages that are low producers of TNFalpha protein when stimulated with interferon gamma, highlighting the physiological importance of 3'UTR elements and their control of mRNA stability. Not only mutations, but also alternative splicing in the 3'UTR can lead to disease as was described for the Wiskott-Aldrich syndrome[26]. Alternative splicing is not necessarily linked to disease though, e.g.…”

A novel large deletion and single nucleotide insertion in the Wiskott–Aldrich syndrome protein gene

“…The polyA signal of wild type WAS , located in exon 12, was absent in the patient's sample as a consequence of the mutation. Stable truncated but nonfunctional protein expression was also detected inducing classical WAS phenotype . In another two intriguing cases, the deletions affected large part of the WAS gene.…”

“…In some of the cases described before, the mutation leads to complete loss of the WASP, while in others a truncated or mutated protein is expressed (WASP positive patients). Deletions in WAS were in most cases identified as short (1–12 bp) whereas the occurrence of large deletions have been rare (Fig. ).…”