X染色体連鎖知的発達障害の分子遺伝学

Molecular genetics of X-linked mental retardation

　精神遅滞（mental retardation：MR）は人口の約3％に認められ，男女比は1.3：1と男性に多い。MRの原因は様々だが，特に中等度以下MR（IQ＜50）の20～25％は遺伝学的要因と考えられている。X染色体上に責任遺伝子を持つX連鎖MR（XLMR）は，臨床的に非特異的XLMR（MRX）と症候性XLMR（MRXS）に分類され，61遺伝子が責任遺伝子として単離されている。MRXの24責任遺伝子（うち6遺伝子はMRXSにも関与）は，（1）Gタンパク質情報伝達に関わる遺伝子，（2）エピジェネティクスを含む遺伝子発現制御に関わる遺伝子，（3）代謝に関わる遺伝子，に大別される。日本国内でのMRリサーチリソースの充実および研究推進が期待される。

　Mental retardation（MR）is one of the most common causes for referral in child-neurological practice. The prevalence of MR is estimated about 3％ of the population, with an approximate male：female ratio of 1.3：1. MR is very heterogeneous, but genetic causes account for 20-25％ of the severe and 5-10％ of the mild forms of MR.

　X-linked mental retardation（XLMR）is divided into“syndromic”form（MRXS）, characterized by MR accompanied somatic, neurologic, behavioral, or metabolic features, and“non-specific”form（MRX）, without such phenotype features. XLMR accounts for 10％ of all MR. Some XLMR genes are responsible for MR,not only of male, but also of female.

　Up to now, more than 60 genes have been identified for XLMR. Twenty-four genes responsible for MRX have been identified so far, and many of them are associated with both MRX and MRXS. The genes are categorized into four mechanism；（1）genes involved in small G protein pathways；Rho GTPases pathway modulating neuronal differentiation and synaptic plasticity（OPHN1, PAK3, ARHGEF6, TM4SF2, FGD1, ARHGEF9）, and Rab GTPases pathway regulating synaptic vesicle cycling（GDI1,IL1RAPL1）,（2）genes involved in epigenetics or gene expression regulation（MECP2, RPS6KA3, ATRX, JARID1C, ZNF41, ZNF81, ZNF674, ARX, FTSJ1, PQBP1, FMR1, FMR2）, （3）genes involved in metabolic pathways（SLC6A8, SLC16A2, FACL4, SMS）, and（4）miscellaneous（AGTR2, DLG, NLGN4, GRIA3）.

　In Japan,Japanese MR research group（Group leader：Dr Yu-ichi Goto, Kodaira, Japan）has been founded since 2003, and more than 80 MR families are registered. It is now establishing a diagnostic system using cytogenetic and molecular genetic methods for MR patients, and searching for new genes responsible for MR.