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A loss‐of‐function mutation in the FTSJ1 gene causes nonsyndromic X‐linked mental retardation in a japanese family
Author(s) -
Takano Kyoko,
Nakagawa Eiji,
Inoue Ken,
Kamada Fumiaki,
Kure Shigeo,
Goto Yuichi
Publication year - 2008
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30638
Subject(s) - frameshift mutation , genetics , biology , mutation , intron , exon , mutant , proband , population , gene , nonsense mutation , microbiology and biotechnology , nonsense mediated decay , rna splicing , medicine , missense mutation , environmental health , rna
Mental retardation (MR) is a common trait, affecting ∼2–3% of individuals in the general population. Although the etiology of MR remains largely unknown, genetics apparently play a major role. Recent molecular studies of X‐linked form of MR in European and North American countries have revealed 24 nonsyndromic X‐linked mental retardation (NS‐XLMR) genes including FTSJ1 , a human homolog of the Escherichia coli 2 ′‐ O ‐rRNA methyltransferase FtsJ/RrmJ gene. Here we identified a novel FTSJ1 mutation in an XLMR family through mutation screening of a cohort of 73 unrelated Japanese male probands with MR. Sequence analysis of the proband and his mother revealed a G > A substitution at the consensus for the donor splicing site in intron 8 (c.571 + 1G > A) of FTSJ1 . This mutation prevented the removal intron 8 from the pre‐mRNA, thereby leading to a frameshift in the mutant FTSJ1 mRNA and resulting in a premature termination in exon 9. Quantitative RT‐PCR showed a significant reduction of mutant FTSJ1 mRNA in the patient's lymphoblast cells, which was restored by treatment with cycloheximide, a potent inhibitor of nonsense‐mediated mRNA decay (NMD). Therefore, mRNAs carrying this mutation are likely subject to degradation by NMD. Together, loss‐of‐function of FTSJ1 may be a mechanism for the cognitive dysfunction observed in this family. Our study also suggested that the FTSJ1 mutation probably accounts for XLMR in Japanese at a similar frequency (1–2%) as in Europeans. © 2007 Wiley‐Liss, Inc.