A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (~7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB-associated disease.
We identified IFIX as a new member of the hematopoietic interferon (IFN)-inducible nuclear protein with the 200-amino-acid repeat (HIN-200) family. Six different alternatively spliced forms of mRNA are transcribed from the IFIX gene, which are predicted to encode six different isoforms of IFIX proteins (IFIXa1, a2, b1, b2, c1, and c2). The IFIX proteins are primarily localized in the nucleus. They share a common N-terminal region that contains a predicted pyrin domain and a putative nuclear localization signal. Unlike IFIXa and IFIXb, IFIXc isoforms do not have the 200-amino-acid signature motif. Interestingly, the expression of IFIX was reduced in most human breast tumors and breast cancer cell lines. Expression of IFIXa1, the longest isoform of IFIX, in human breast cancer cell lines reduced their anchoragedependent and -independent growth in vitro and tumorigenicity in nude mice. Moreover, a liposome-mediated IFIXa1 gene transfer suppressed the growth of alreadyformed tumors in a breast cancer xenograft model. IFIXa1 appears to suppress the growth of breast cancer cells in a pRB-and p53-independent manner by increasing the expression of the cyclin-dependent kinase inhibitor p21 CIP1 , which leads to the reduction of the kinase activity of both Cdk2 and p34
Cdc2. Together, our results show that IFIXa1 possesses a tumor-suppressor activity and suggest IFIXa1 may be used as a therapeutic agent in cancer treatment.
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