Choucair Nancy, Mignon-Ravix Cecile, Cacciagli Pierre, Abou Ghoch Joelle, Fawaz Ali, Mégarbané André, Villard Laurent, Chouery Eliane
Unité de Génétique Médicale et Laboratoire Associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, rue de Damas B.P. 17-5208 Mar Mikhael, Beyrouth, 11042020 Lebanon ; Aix-Marseille Université, GMGF, Marseille, France ; INSERM, UMR_S 910, Marseille, France.
Aix-Marseille Université, GMGF, Marseille, France ; INSERM, UMR_S 910, Marseille, France.
Mol Cytogenet. 2015 Jun 16;8:39. doi: 10.1186/s13039-015-0149-0. eCollection 2015.
The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID).
We describe a 30 month old boy with severe intellectual disability, trigonocephaly and dysmorphic facial features such as a midface hypoplasia, a flat nose, a depressed nasal bridge, hypertelorism, a long philtrum and a drooping mouth. Microarray chromosomal analysis revealed the presence of a homozygous deletion involving the PTPRD gene, located on chromosome 9p22.3. Reverse Transcription PCR (RT-PCR) amplifications all along the gene failed to amplify the patient's cDNA in fibroblasts, indicating the presence of two null PTPRD alleles. Synaptic PTPRD interacts with IL1RAPL1 which defects have been associated with intellectual disability (ID) and autism spectrum disorder. The absence of the PTPRD transcript leads to a decrease in the expression of IL1RAPL1. These results suggest the direct involvement of PTPRD in ID, which is consistent with the PTPRD -/- mice phenotype. Deletions of PTPRD have been previously suggested as a cause of trigonocephaly in patients with monosomy 9p and genome-wide association study suggested variations in PTPRD are associated with hearing loss.
The deletion identified in the reported patient supports previous hypotheses on its function in ID and hearing loss. However, its involvement in the occurrence of metopic synostosis is still to be discussed as more investigation of patients with the 9p monosomy syndrome is required.
额缝过早融合会导致三角头畸形的临床表型。这种特征与9p单体综合征之间的关联已得到充分证实，位于9p24.1p23区域且编码兴奋性和抑制性突触组织主要成分的受体型蛋白酪氨酸磷酸酶基因（PTPRD），被认为是导致这种颅缝早闭形式的一个良好候选基因。此外，已知PTPRD可招募多个突触后伴侣，如IL1RAPL1，其基因改变会导致非综合征性智力障碍（ID）。
我们描述了一名30个月大的男孩，患有严重智力障碍、三角头畸形以及面部畸形特征，如面中部发育不全、扁平鼻、鼻梁凹陷、眼距过宽、人中长和嘴角下垂。微阵列染色体分析显示存在一个纯合缺失，涉及位于9号染色体p22.3上的PTPRD基因。沿该基因进行的逆转录聚合酶链反应（RT-PCR）扩增未能在成纤维细胞中扩增出患者的cDNA，表明存在两个无效的PTPRD等位基因。突触PTPRD与IL1RAPL1相互作用，IL1RAPL1的缺陷与智力障碍（ID）和自闭症谱系障碍有关。PTPRD转录本的缺失导致IL1RAPL1表达下降。这些结果表明PTPRD直接参与了ID的发生，这与PTPRD基因敲除小鼠的表型一致。先前已提出PTPRD缺失是9p单体患者三角头畸形的一个原因，全基因组关联研究表明PTPRD的变异与听力损失有关。
在所报道患者中鉴定出的缺失支持了先前关于其在ID和听力损失中功能的假设。然而，由于需要对9p单体综合征患者进行更多研究，其在额缝早闭发生中的作用仍有待讨论。
