The Reduced Expression of the HADH2 Protein Causes X-Linked Mental Retardation, Choreoathetosis, and Abnormal Behavior
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- 作者：Claus Lenski ; R. Frank Kooy ; Edwin Reyniers ; Daniela Loessner ; Ronald J.A. W ; ers ; Birgitta Winnepenninckx ; Heide Hellebr ; Stefanie Engert ; Charles E. Schwartz ; Alfons Meindl ; Juliane Ramser
- 刊名：The American Journal of Human Genetics
- 出版年：2007
- 出版时间：February 2007
- 年：2007
- 卷：80
- 期：2
- 页码：372-377
- 全文大小：4316 K
文摘
Recently, we defined a new syndromic form of X-linked mental retardation in a 4-generation family with a unique clinical phenotype characterized by mild mental retardation, choreoathetosis, and abnormal behavior (MRXS10). Linkage analysis in this family revealed a candidate region of 13.4 Mb between markers DXS1201 and DXS991 on Xp11; therefore, mutation analysis was performed by direct sequencing in most of the 135 annotated genes located in the region. The gene (HADH2) encoding l-3-hydroxyacyl-CoA dehydrogenase II displayed a sequence alteration (c.574 C→A; p.R192R) in all patients and carrier females that was absent in unaffected male family members and could not be found in 2,500 control X chromosomes, including in those of 500 healthy males. The silent C→A substitution is located in exon 5 and was shown by western blot to reduce the amount of HADH2 protein by 60 % –70 % in the patient. Quantitative in vivo and in vitro expression studies revealed a ratio of splicing transcript amounts different from those normally seen in controls. Apparently, the reduced expression of the wild-type fragment, which results in the decreased protein expression, rather than the increased amount of aberrant splicing fragments of the HADH2 gene, is pathogenic. Our data therefore strongly suggest that reduced expression of the HADH2 protein causes MRXS10, a phenotype different from that caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, which is a neurodegenerative disorder caused by missense mutations in this multifunctional protein.