The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2.

Abstract

Fragile X Mental Retardation Syndrome is the most common form of hereditary mental retardation, and is caused by defects in the FMR1 gene. FMR1 is an RNA‐binding protein and the syndrome results from lack of expression of FMR1 or expression of a mutant protein that is impaired in RNA binding. The specific function of FMR1 is not known. As a step towards understanding the function of FMR1 we searched for proteins that interact with it in vivo. We have cloned and sequenced a protein that interacts tightly with FMR1 in vivo and in vitro. This novel protein, FXR2, is very similar to FMR1 (60% identity). FXR2 encodes a 74 kDa protein which, like FMR1, contains two KH domains, has the capacity to bind RNA and is localized to the cytoplasm. The FXR2 gene is located on human chromosome 17 at 17p13.1. In addition, FMR1 and FXR2 interact tightly with the recently described autosomal homolog FXR1. Each of these three proteins is capable of forming heteromers with the others, and each can also form homomers. FXR1 and FXR2 are thus likely to play important roles in the function of FMR1 and in the pathogenesis of the Fragile X Mental Retardation Syndrome.

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…Alternative splicing in exons 12, 14, 15, 17, and in the 3' untranslated region result in several isoforms of the encoded protein, FMRP (D'Hulst and ). Fmr1 along with gene family members fragile X related gene 1 and 2 (Fxr1 and Fxr2) are highly conserved among vertebrates (Zhang et al, 1995). The Fmr1 gene contains a TATA-less promoter region and three initiator-like sequences that correspond to three transcription start sequences (Weis and Reinberg, 1992;Chow et al, 1995).…”

New insights into fragile X syndrome: from molecules to neurobehaviors

“…FMRP, and its autosomal paralogs the fragile-X-related protein FXR1P and FXR2P, consists of a small family of RNA-binding proteins (fragile X-related gene family) [5,6]. These proteins share .…”

Chromosomal fragility and human genetic disorders

“…Finally, the Z alleles can undergo massive expansions to form full mutation (L) alleles,resulting in fragile X syndrome.Evidence for this hypothesis comes from the fact that PCR amplification of the CGG repeat region in the normal control as well as the premutation alleles followed by sequence analysis shows the highest variability of the pure repeat lengths among the controls occuring at the 3' end. In one of the studies all the premutation alleles showed _>50 pure CGG repeats while a majority of the controls hardly had _> 40 repeats (28).…”

“…The fact that FMR1 is expressed in actively dividing cells, cosediments with 60s ribosomes and strongly interacts with Rab40, a protein found in the nuclear pores seem to support its postulated function (31). FMRP also interacts with the autosomal proteins with identical RNA binding motifs, FXR1 and FXR2, The non-lethal effects of the lack of FMR1 may be due to the redundancy of its function (28).…”

“…The exact function of the protein is not known, but it shares extensive homology with certain proteins containing RNA binding domain such as the Rev protein of HIV, hnRNPA1, a protein found Ubiquitously and two autosomal proteins FXR1 and FXR2. FMR-1 forms a heteromer with FXR 1 and FXR2 (28). About 4% of all the mRNAs in fetal tissues is bound by FMRR Apart from the RNA binding domains, FMRP has a N-terminal KKXKP, a nuc, lear localization signal (NLS) and a 17 amino acid sequence in the exon 14 that is a nuclear export signal (NES).…”