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Does the P 172 H Mutation at the TM 4 SF 2 Gene Cause X-Linked Mental Retardation ?

The TM4SF2 gene mapped at Xp11.4 has recently been associated with non-syndromic X-linked mental retardation (MRX) by the analysis of the breakpoint of a t(X;2) balanced translocation in a female patient with mild mental retardation and minor autistic features [Zemni et al., 2000]. To date, three TM4SF2 mutations have been identified in three familial cases of MRX: the G218X (family L28), the P172H (family T15) [Zemni et al., 2000], and, more recently, a deletion of 2bp (564delGT) in exon 5 (familyMRX58) [Abidi et al., 2002]. Two of these changes create a premature stop codon and it has been predicted that theMRX in these cases results from the deficiency of the TM4SF2 product. The family T15, first described by Zemni et al. [2000], was recently reevaluated [Gomot et al., 2002]. Neuropsychological evaluation showed that five out of seven males and one of three women had mild to moderate mental retardation. The mutation was present in all mentally impaired individuals and also in one male reported to be normal. Further segregation analysis of markers surrounding the TM4SF2 gene suggested that in this family the disease gene should be localized between loci DXS556 (Xp11.4) and DXS441 (Xq13.2), thus excluding theTM4SF2 gene. The authors put forward two alternative explanations: (1) the TM4SF2 P172H mutation would be the cause of MR in association with intra-familial phenotypic variability or (2) this would be a rare mutation not detrimental to the functioning of theTM4SF2protein, and thereforenot causative of the phenotype [Gomot et al., 2002]. As part of an X-linked mental retardation (XLMR) candidate gene testing, we screened the seven exons of the TM4SF2 gene in 105males withmental retardation (25 familial and 80 isolated cases), whowere not carriers of the fragile X mutation. Blood samples were collected after informed consent. All the coding exons of the TM4SF2 gene were amplified using the primers and PCR conditions reported elsewhere [Zemni et al., 2000], and the amplification products were analyzed by SSCP (single strand conformation polimorfism) according to Splendore et al. [2000].One sample showedanabnormal migration pattern for the fragment corresponding to exon 5 (data not shown). Sequencing in both directions was performed using the BigDye Terminator Cycle Sequencing Kit (PE Biosystems, Foster City, CA) in an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA). A C!A transversion was found at nucleotide c.515 leading to the Pro!His substitution of amino acid 172 (P172H) (Fig. 1). This result was confirmed by the single-nucleotide primer extension assay (SNuPe, Amersham Biosciences, Piscataway, USA), a method that precisely localizes a SNP site. The patientwith the P172Hwas examined at 21 years of age and presented with mild to moderate mental retardation. He is able to write and read only simple texts. Developmental milestones had been slightly delayed, but speech acquisition was severely impaired, since he started talking at 31⁄2 years. Dysmorphic features included: a long narrow face with pronounced oral hypotonia; short forehead and filtrum; high palate; teeth malocclusion; abnormally folded ears; depressed sternum; hypoplastic nails; somewhat scarce hair with alopecia spots. Ophthalmological findings included nystagmus and myopia. His mother and sister, both withnormal intelligence,were found to be carriers of the P172H mutation, but not his mentally normal brother (Fig. 2). This mutation was not detected in the SNuPe assay screening of additional 320 unrelated X chromosomes from normal males. The finding of the mutation in a cohort of 105 individuals with mental retardation but not in 320 normalmenwith a similar ethnic background further supports the hypothesis that this might be a pathogenic mutation. A possibility of this being a common polymorphism has also been ruled out by Zemni et al. [2000] as they did not find it in 100 normal chromosomes. Gomot et al. [2002] advanced the possibility that thismutationwas not the cause ofmental retardation in family T15 because they found one mentally normal male carrier, an individual who has been previously Grant sponsor: FAPESP; Grant sponsor: PRONEX; Grant sponsor: CNPq.