Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure

Abstract

Structural chromosome abnormalities have aided in gene identification for over three decades. Delineation of the deletion sizes and rearrangements allows for phenotype/genotype correlations and ultimately assists in gene identification. In this report, we have delineated the precise rearrangements in four subjects with deletions, duplications, and/or triplications of 1p36 and compared the regions of imbalance to two cases recently published. Fluorescence in situ hybridization (FISH) analysis revealed the size, order, and orientation of the duplicated/triplicated segments in each subject. We propose a premeiotic model for the formation of these complex rearrangements in the four newly ascertained subjects, whereby a deleted chromosome 1 undergoes a combination of multiple breakage-fusion-bridge (BFB) cycles and inversions to produce a chromosome arm with a complex rearrangement of deleted, duplicated and triplicated segments. In addition, comparing the six subjects' rearrangements revealed a region of overlap that when triplicated is associated with craniosynostosis and when deleted is associated with large, late-closing anterior fontanels. Within this region are the MMP23A and -B genes. We show MMP23 gene expression at the cranial sutures and we propose that haploinsufficiency results in large, late-closing anterior fontanels and overexpression results in craniosynostosis. These data emphasize the important role of cytogenetics in investigating and uncovering the etiologies of human genetic disease, particularly cytogenetic imbalances that reveal potentially dosage-sensitive genes.

Monosomy 1p36 uncovers a role for OX40 in survival of activated CD4+ T cells

“…The syndrome occurs in 1:5000 births and is characterized by a phenotype including deep-set eyes, midfacial hypoplasia, asymmetric ears and pointed chin. Other clinical associations may include seizures, hypothyroidism, cardiomyopathy, developmental delay, hearing impairment and mental retardation [2,3,4,5]. To date, immunodeficiency has not been reported in these patients, however genes for various immunologically important members of the TNFR superfamily are located in or near the region of 1p36.…”

Pesquisa dos mecanismos de rearranjos cromossômicos subteloméricos na monossomia 1p36, expansão do espectro da variabilidade fenotípica e comportamental, diagnósticos diferenciais e caracterização de uma região crítica para obesidade

“…Entretanto, alguns genes candidatos são o proto-oncogene SKI e o fator 10 de biogênese dos peroxissomos (PEX10) , a subunidade beta do canal de potássio (KCNAB2) (Heilstedt et al 2001), o gene 23 da matrix metaloproteína (MMP23) (Gajecka et al 2005) e a subunidade delta do receptor A do ácido gama-aminobutírico (GABRD) . Considera-se que a monossomia 1p36 seja uma síndrome de deleção de genes contíguos ) e, regiões críticas foram sugeridas para algumas características clínicas (Heilstedt et al 2003a).…”

“…No outro caso, o microarray não detectou nenhum ganho de cópia que, portanto, foi estimado abaixo do nível de resolução do teste (<100 kb). Em outro trabalho, Gajecka et al (2005) descreveu mais 4 casos de rearranjos complexos envolvendo deleções terminais associadas com segmentos proximais em 1p36 duplicados ou triplicados e caracterizados por array CGH.…”

“…Atualmente, os genes candidatos para algumas características da síndrome de monossomia 1p36 são o proto-oncogene SKI e o fator 10 de biogênese dos peroxissomos (PEX10) , a subunidade beta do canal de potássio (KCNAB2) (Heilstedt et al 2001), o gene 23 da matrix metaloproteína (MMP23) (Gajecka et al 2005) e a subunidade delta do receptor A do ácido gamaaminobutírico (GABRD) .…”

“…Atualmente, após a primeira demonstração por Flint et al (1995) da contribuição de rearranjos subteloméricos crípticos na etiologia destas condições, a freqüência de rearranjos subteloméricos patogênicos em pacientes com RM inespecífico esta confirmada em ~2.5% (Ledbetter e Martin 2007) Apenas recentemente os mecanismos de origem de rearranjos subteloméricos começaram a ser investigados, graças à clonagem e seqüenciamento dos pontos de quebra em poucas deleções terminais, especialmente, as deleções envolvendo a região cromossômica 1p36 Ballif et al 2004a e b;Gajecka et al 2005;Gajecka et al 2006a e b;Rooms et al 2006;Gajecka et al 2008).…”