Novel microduplications at Xp11.22 including HUWE1: clinical and molecular insights into these genomic rearrangements associated with intellectual disability

Abstract

Recently, we defined a minimal overlapping region for causal Xp11.22 copy number gains in males with intellectual disability (ID), and identified HECT, UBA and WWE domain-containing protein-1 (HUWE1) as the primary dosage-sensitive gene, whose overexpression leads to ID. In the present study, we used this minimal interval to search for HUWE1 copy number variations by quantitative polymerase chain reaction in a large cohort of Brazilian males with idiopathic ID. We detected two unrelated sporadic individuals with syndromic ID carrying unique overlapping duplications encompassing HUWE1. Breakpoint junction analysis showed a simple tandem duplication in the first patient, which has probably arisen by microhomology-mediated break-induced repair mechanism. In the second patient, the rearrangement is complex having an insertion of an intrachromosomal sequence at its junction. This kind of rearrangement has not been reported in Xp11.22 duplications and might have emerged by a replication- or recombination-based mechanism. Furthermore, the presence of infantile seizures in the second family suggests a potential role of increased KDM5C expression on epilepsy. Our findings highlight the importance of microduplications at Xp11.22 to ID, even in sporadic cases, and reveal new clinical and molecular insight into HUWE1 copy number gains.

HUWE1 plays important role in mouse preimplantation embryo development and the dysregulation is associated with poor embryo development in humans

“…HUWE1 is a HECT domain containing ubiquitin ligase, and recent studies showed that it plays important roles in cancer development, spermatogenesis and stem cell differentiation1261415. In the current study, our result shows that Huwe1 is expressed in mouse preimplantation embryo, and its expression is regulated by low oxygen concentration during early embryo development.…”

“…Cul4b, an X-linked mental retardation protein, was also shown to be critical for extra-embryonic tissue development, while dispensable for embryo proper development2122. Since both Cul4b and HUWE1 are involved in the X-linked mental retardation, it would be interesting to generate embryo specific and extra-embryonic tissue specific knock out mice and check whether they have neuron specific phenotype2614. It would also be valuable to check the three layers’ development in Huwe1 knock out embryo.…”

Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease

“…Importantly, this study also performed qPCR and showed that HUWE1 expression levels were elevated in these patient samples, consistent with an overexpression/gain-of-function effect on HUWE1. Subsequent studies that used exome or next generation sequencing identified HUWE1 CNVs in numerous other families with non-syndromic ID [66][67][68][69][70][71][72][73][74][75] (Table 1).…”

“…Individuals with HUWE1 CNVs sometimes have other neurodevelopmental conditions that accompany ID. The most compelling links are to epilepsy or seizure [64,67,[69][70][71][72][73][74]. Autism-like behaviors have also been documented [66,70,72].…”

Xp11.22 Microduplications Including HUWE1: Case Report and Literature Review

“…Different cases of Xp duplication, that include the duplicated region described here, have been reported. 6,7,[20][21][22][23][24][25][26][27][28][29][30][31][32] However, in most cases a larger part of Xp, compared with our submicroscopic duplication, is involved. In our patient, the size of duplicated region of Xp is 363 kb and it extends from 53.475.904 nucleotide to 53.838.767 nucleotide.…”