Copy-Number Mutations on Chromosome 17q24.2-q24.3 in Congenital Generalized Hypertrichosis Terminalis with or without Gingival Hyperplasia

Abstract

Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

“…The Carney Complex is characterized by pigmented lesions of the skin and mucosae, myxomas, endocrine tumors or endocrine overactivity and schwannomas. Sun et al 14 reported three Han Chinese families with congenital generalized hypertrichosis terminalis segregating with a small microdeletion involving chromosome bands 17q24.2-q24.3 for which MAP2K6 (mitogen-activated protein kinase kinase 6) was the best candidate gene. Here we present four previously unreported patients with overlapping microdeletions at chromosome band 17q24.2.…”

Genomic analysis of gum disease and hypertrichosis in foxes

“…The original interest in the 17q24.2-24.3 chromosomal region was in the MAP2K6 gene (Sun et al, 2009). While other MAPK pathway proteins have been implicated in both hair growth and gingival overgrowth conditions, there was some debate about the MAP2K6 gene involvement in the combined phenotype (Hart et al, 2002;Sun et al, 2009).…”

“…It is associated with chromosomal region 17q24.2-24.3 (Sun et al, 2009). Of interest, this region contains several members of the ATP binding cassette transporter family A (ABCA) family of genes, MAP2K6, and the PITPNC1 gene.…”

“…KCNJ8 and KCNJ11 microarray gene expression levels were examined and neither showed any statistically significant differential expression (P < 0.10). Hypertrichosis with gingival fibromatosis is associated with the chromosome region 17q24.2-q24.3 in humans (Sun et al, 2009) and this region contains the following genes: ABCA5, ABCA6, ABCA10 and MAP2K6. ABCA10 was not on the Affymetrix GeneChip Canine Genome 2.0 Array, nor was a description of the gene found in NCBI for canines.…”

“…We conducted an extensive review of the congenital forms of hypertrichosis with gingival fibromatosis in humans and examined their known chromosomal regions and in the context of the HHG microarray expression patterns. In addition we report candidate gene sequencing based mutational analysis of the mitogen activated protein kinase kinase 6 (MAP2K6) gene in the silver fox, for which a role in hypertrichosis has been debated (Sun et al, 2009). …”