Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation

Abstract

Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.

HUWE1 mutation explains phenotypic severity in a case of familial idiopathic intellectual disability

“…In this study, high-throughput sequencing of the coding regions of the X-chromosome led to the identification of a missense variant in the HUWE1 gene. The same variant has been reported before by Froyen et al (2008). We compare the phenotypes and demonstrate that, in the present family, the HUWE1 mutation segregates with the more severe ID phenotypes of two out of three brothers.…”

“…In contrast to PABPC5, HUWE1 is an established XLID gene and the same missense mutation has been reported before by Froyen et al [13]. Therefore, we classified the HUWE1 mutation as the pathological mutation in this family.…”

“…Patients with a duplication involving HUWE1 are usually described to have a nonsyndromic mild to moderate ID [13,15]. Few affected individuals are reported to have minor dysmorphic features, but a consistent pattern among all duplication carriers is lacking.…”

“…Copy number variants as well as missense mutations of HUWE1 have previously been reported in individuals with XLID [13]. This study deals with a comparison of the clinical features and further reinforcement of HUWE1 as an XLID gene.…”

Implications of gene copy-number variation in health and diseases

“…Further, it was noted that this duplication covered a 320-kb region involving four genes (SMC1A, RIBC1, HSD17B10 and HUWE1), three candidates of which may convey the phenotype of MR. 19 Apart from duplication, many other forms of genetic variations such as point mutation in SMC1A and HUWE1 genes and a silent mutation in HSD17B10 gene conveyed the phenotypes of MR along with other distinguished characteristic. 20 The conclusion drawn from the above findings showed that it is a dosagesensitive gene, which confers the MR phenotype in the patients with duplicated genes. MECP2, X-linked methyl-CpG-binding protein 2 gene at Xq28 is also found to be associated with the developmental delay, MR and fatal infantile encephalopathy in males, and recently it has been reported that low copy number of MECP2 gene confers a clinical phenotype, resulting in MR or developmental delay and altered neurological symptoms (particularly seizures) phenotypes in males.…”