Characterization of a de novo balanced t(4;20)(q33;q12) translocation in a patient with mental retardation

Abstract

CHD6 is an ATP-dependent chromatin-remodeling enzyme, which has been implicated as a crucial component for maintaining and regulating chromatin structure. CHD6 belongs to the largest subfamily, subfamily III (CHD6-9), of the chromodomain helicase DNA (CHD-binding protein) family of enzymes (CHD1-9). Here we report on a female patient with a balanced translocation t(4;20)(q33;q12) presenting with severe mental retardation and brachydactyly of the toes. We identified the translocation breakpoint in intron 27 of CHD6 at 20q12, while the 4q33 breakpoint was intergenic. Northern blot analysis demonstrated the CHD6 mRNA in the patient's lymphoblastoid cells was decreased to ∼50% of the control cells. To investigate the cellular mechanism of diseases resulting from decreased CHD subfamily III proteins, we knocked down CHD6 or CHD7 by RNA interference in HeLa cells and analyzed chromosome alignment. The both CHD6- and CHD7-knockdown cells showed increased frequency of misaligned chromosomes on metaphase plates. Moreover, an elevated frequency of aneuploidy, the major cause of miscarriages and mental retardation, was observed in patients with CHD6 and CHD7 haploinsufficiency. These results suggest that CHD6 and CHD7 play important roles in chromatin assembly during mitosis and that mitotic delay and/or impaired cell proliferation may be associated with pathogenesis of the diseases caused by CHD6 or CHD7 mutations.

CHD6 (chromodomain helicase DNA binding protein 6)

“…Mutations have been identified in several types of cancer, however, no nonsense or frameshift mutations exclusive to CHD6 have been associated with cancer to date (Cosmic database). Haploinsufficiency in CHD6 has been reported in miscarriage and mental retardation (Yamada et al, 2010) and mutation of the ATPase region in mice resulted in an ataxia phenotype (Lathrop et al, 2010).…”

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

“…CHD proteins in autism spectrum disorder, intellectual disability, and epilepsy Application of cytogenetic and next-generation sequencing technologies to large cohorts of individuals with autism spectrum disorder (ASD), intellectual disability (ID), and/or epilepsy has uncovered de novo and inherited heterozygous frameshift, nonsense, or copy dosage mutations in several CHD genes, including CHD2, CHD6, CHD7, and CHD8 [66][67][68][69][70][71][72][73][74]. For CHD2, CHD6, and CHD7, mutations identified thus far are nonrecurrent (present in only individual cases), private mutations that account for a small fraction of ASD/ ID/epilepsy cases.…”

Aneuploidy and Intellectual Disability

“…CHD6 associates with many proteins to form a large protein complex (>2 MDa) (Lutz et al, 2006). This finding and the diffused distribution of CHD6 at metaphase (Yamada et al, 2010) suggest that the protein complex may act as a basis for the formation and/or stabilization of the mitotic spindle structure.…”

“…An increased rate of aneuploidy was also identified in a patient with chromodomain helicase DNA (CHD)-6 haploinsufficiency (S6) and in 2 patients with CHARGE syndrome (manifestations are coloboma of the eye (Table 3) (Yamada et al, 2010). Both proteins are ATP-dependent chromatin-remodeling enzymes and play important roles in maintaining and regulating chromatin structure.…”

“…Lymphoblastoid cells from the patients with CHD6 or CHD7 haploinsufficiency, and CHD6 or CHD7 knockdown HeLa cells, display aneuploidy and an increased frequency of misaligned chromosomes, respectively (Fig. 1, Table 3) (Yamada et al, 2010). CHD6 associates with many proteins to form a large protein complex (>2 MDa) (Lutz et al, 2006).…”