Members of the AFF (AF4/FMR2) family of putative transcription factors are involved in infant acute leukaemia and intellectual disability (ID), although very little is known about their transcriptional targets.
We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXEID.
These results suggest that FMR2 is an upstream regulator of FOS and JUN, and further link deregulation of the immediate early response genes to the pathology of ID- and FRAXE-associated ID in particular.
AFF2/FMR2 is silenced in FRAXEintellectual disability, while the other three members have been reported to form fusion genes as a consequence of chromosome translocations with the myeloid/lymphoid or mixed lineage leukemia (MLL) gene in acute lymphoblastic leukemias (ALLs).
With the forthcoming identification of the gene targets that trigger Purkinje cell death in the robotic cerebellum, and the functional conservation among the ALF proteins, the robotic mouse promises to deliver important insights into the pathogenesis of human ataxia, but also of mental retardation to which FMR2 and LAF4 have been linked.
In contrast, a relationship between the second main group of fragile sites characterized by repeat expansion, the rare fragile sites, and mental retardation has been proposed many years ago, but after the molecular cloning of FRAXA and FRAXE both unequivocally involved in mental retardation, no additional fragile sites linked with mental retardation have been cloned for over a decade.
Reverse transcriptase PCR studies on the FMR2 and FMR3 genes showed that only the FMR3 gene transcription was abolished, suggesting a possible causal relationship between the lack of FMR3 expression and mental retardation in this patient.
The mutated protein, Af4, is a member of the AF4/LAF4/FMR2 (ALF) family of putative transcription factors previously implicated in childhood leukaemia and FRAXEmental retardation.
Here we report molecular screening survey of 97 unrelated individuals diagnosed with non-specific mental retardation (MR), which produced positive test for FRAXA in two boys and none positive for the FRAXE mutation.
FRAXE syndrome is distinct from fragile X syndrome, a more common genetic form of mental retardation caused by expansion and methylation of a similar repeat in the FMR1 gene located 600 kb proximal to FRAXE.
Three individuals (2.6%) with the FRAXA form of the fragile X syndrome and one boy (0.9%) with FRAXEmental retardation were detected; a total of four newly diagnosed fragile X families were identified.
So far, seven X-chromosomal genes mutated in nonspecific mental retardation (MRX) have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPHN1 and PAK3 (refs 2-9).
The aim of this population screening study was to determine if Fra-X or FRAXE mutations are the cause of a number of cases of mental retardation in a sample of Mexican children with mental retardation of unknown cause (MRUC) and to stress the importance of performing molecular analysis of the FMR-1 gene in all patients with MRUC.
The presence of a phenotypically normal male with absent FMR2 expression in fibroblasts suggests that the relationship between the FRAXE mutation, FMR2 expression and MR needs to be further investigated.
This review summarises the new data on FRAXE associated mental retardation and the FMR2 gene in the light of the recent discoveries of new genes responsible for other forms of non-specific X-linked mental retardation.
We examined the prevalence of the fragile X mental retardation (FMR1) full mutation and fragile X E mutation (FMR2) among preschoolers evaluated for language delay.
The FRAXE fragile site, 600 Kb distal to the more common FRAXA, has been reported to be expressed in subjects with mild nonsyndromal mental retardation.