SEVERE MENTAL-RETARDATION AND MACROORCHIDISM WITHOUT MUTATION IN THE FMR1 GENE

Only one missense mutation, an Ile304Asn, has been reported in the fra gile X gene (FMR1). This mutation is located in the second IIR domain of FMR1, and has led to the discovery of the function of the FMR1 gene product as an RNA-binding protein. The patient carrying this mutation has profound mental retardation, macroorchidism, and an ''acromegalic '' face with prominent supraorbital ridges, enlarged jaw, heavy brow r idges, thick lips, and a broad nose. We have studied the possible invo lvement of FMR1 in two maternal half-brothers with a phenotype similar to that of the patient with the Ile304Asn mutation. Both brothers had an identical number of CGG repeats in the normal size-range, and shar ed the same maternal Xq27 haplotype. Southern blot analysis with two o verlapping FMR1 cDNA clones, spanning the total FMR1 open reading fram e, showed no major deletions, insertions, or gross rearrangements. Sin gle-strand conformation pattern (SSCP) analysis of the KH domains show ed no aberrant patterns. The total open reading frame of the FMR1 gene was cloned and sequenced, but no mutation was found. Northern blot an alysis showed mRNA in the normal size-range, and immunocytochemistry o n individual lymphocytes indicated that FMRP, the protein product of F MR1, was present. In conclusion, it is unlikely that FMR1 plays a role in the phenotype of this patient. Other genes may be responsible for the combination of mental retardation and macroorchidism. (C) 1996 Wil ey-Liss, Inc.