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Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis.

ABSTRACT: Herein we characterize an apparently balanced de novo translocation, t(X;15)(p22.2;q26.1)dn, in a female patient with scoliosis, hirsutism, learning problems, and developmental delay (DGAP025). Other clinical findings include a high-arched palate, 2-3 syndactyly of the toes, and mildly elevated serum testosterone. No known or predicted genes are disrupted by the Xp22.2 breakpoint. The 15q26.1 breakpoint disrupts chromodomain helicase DNA binding protein 2 (CHD2). Another member of the chromatin-remodeling gene family, CHD7, has been associated with a defined constellation of congenital anomalies known as coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies syndrome (CHARGE) and idiopathic scoliosis. Monosomy of 15q26 also has been associated with a spectrum of congenital abnormalities and growth retardation that overlaps with those of DGAP025. To provide a biological correlate, we characterized a mutant mouse model with Chd2 disruption that is associated with embryonic and perinatal lethality. Expression analysis indicated that Chd2 is expressed in the heart, forebrain, extremities, facial and dorsal regions during specific times of embryonic development. Chd2(+/m) mice showed pronounced lordokyphosis, reduced body fat, postnatal runting, and growth retardation. These data suggest that haploinsufficiency for CHD2 could result in a complex of abnormal human phenotypes that includes scoliosis and possibly features similar to CHARGE syndrome.

SUBMITTER: Kulkarni S

PROVIDER: S-EPMC2834558 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis.

Kulkarni Shashikant S Nagarajan Prabakaran P Wall Jonathan J Donovan Diana J DJ Donell Robert L RL Ligon Azra H AH Venkatachalam Sundaresan S Quade Bradley J BJ

American journal of medical genetics. Part A 20080501 9

Herein we characterize an apparently balanced de novo translocation, t(X;15)(p22.2;q26.1)dn, in a female patient with scoliosis, hirsutism, learning problems, and developmental delay (DGAP025). Other clinical findings include a high-arched palate, 2-3 syndactyly of the toes, and mildly elevated serum testosterone. No known or predicted genes are disrupted by the Xp22.2 breakpoint. The 15q26.1 breakpoint disrupts chromodomain helicase DNA binding protein 2 (CHD2). Another member of the chromatin- ...[more]

PMID: 18386809

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Project description:Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4-the core component of the nucleosome remodeling and deacetylase (NuRD) complex-may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either 'deleterious', 'probably/possibly damaging' or as 'high/medium pathogenic'; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.

Dataset Information

Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis.

Publications

Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis.

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