Cantagrel V, Lossi A-M, Boulanger S, Depetris D, Mattei M-G, Gecz J, Schwartz C E, Van Maldergem L, Villard L
Inserm U491, Faculté de Médecine de La Timone, 27, Bd. Jean Moulin, 13385 Marseille Cedex 5, France.
J Med Genet. 2004 Oct;41(10):736-42. doi: 10.1136/jmg.2004.021626.
Mental retardation (MR) affects 2-3% of the human population and some of these cases are genetically determined. Although several genes responsible for MR have been identified, many cases have still not been explained.
We have identified a pericentric inversion of the X chromosome inv(X)(p22.3;q13.2) segregating in a family where two male carriers have severe MR while female carriers are not affected.
The molecular characterisation of this inversion led us to identify two new genes which are disrupted by the breakpoints: KIAA2022 in Xq13.2 and P2RY8 in Xp22.3. These genes were not previously fully characterised in humans. KIAA2022 encodes a protein which lacks significant homology to any other known protein and is highly expressed in the brain. P2RY8 is a member of the purine nucleotide G-protein coupled receptor gene family. It is located in the pseudo-autosomal region of the X chromosome and is not expressed in brain.
Because the haploinsufficiency of P2RY8 in carrier mothers does not have a phenotypic consequence, we propose that the severe MR of the affected males in this family is due to the absence of the KIAA2022 gene product. However, screening 20 probands from X linked MR families did not reveal mutations in KIAA2022. Nonetheless, the high expression of this gene in fetal brain and in the adult cerebral cortex could be consistent with a role in brain development and/or cognitive function.
智力迟钝（MR）影响2%至3%的人群，其中一些病例是由基因决定的。尽管已经确定了几个导致智力迟钝的基因，但仍有许多病例无法解释。
我们在一个家族中发现了X染色体的臂间倒位inv(X)(p22.3;q13.2)，该家族中有两名男性携带者患有严重智力迟钝，而女性携带者未受影响。
对该倒位的分子特征分析使我们鉴定出两个被断点破坏的新基因：位于Xq13.2的KIAA2022和位于Xp22.3的P2RY8。这些基因以前在人类中未得到充分表征。KIAA2022编码一种与任何其他已知蛋白质均无显著同源性的蛋白质，且在大脑中高度表达。P2RY8是嘌呤核苷酸G蛋白偶联受体基因家族的成员。它位于X染色体的假常染色体区域，在大脑中不表达。
由于携带者母亲中P2RY8的单倍剂量不足没有表型后果，我们认为该家族中受影响男性的严重智力迟钝是由于KIAA2022基因产物缺失所致。然而，对20个X连锁智力迟钝家族的先证者进行筛查未发现KIAA2022存在突变。尽管如此，该基因在胎儿脑和成年大脑皮质中的高表达可能与大脑发育和/或认知功能中的作用一致。
