"Identifying Modifier Genes for Otx2 Deficiency in Embryonic Head Development"
Combined Pituitary Hormone Deficiency (CPHD) is a common cause of endocrine referral in children. It is defined as deficiency of growth hormone and at least one other pituitary hormone. Some cases are associated with defects in craniofacial development. Up to 30 genes are implicated in CPHD, but over 80% of the cases have no known cause (1). There are examples of X-linked and autosomal recessive inheritance, and cases of dominant loss of function with incomplete penetrance are common. The variable penetrance of CPHD suggests the influence of other genetic or environmental factors.
Orthodenticle homeobox 2 (OTX2) is important for embryonic head development and is a known CPHD causal gene that is dominant with incomplete penetrance in human and mouse pedigrees. When mutated, OTX2 can cause severe craniofacial malformations, eye and brain defects, and/or CPHD. Mouse studies revealed that genetic background can enhance or suppress the effects of Otx2 haploinsufficiency. Genetic mapping studies identified two loci that affect mandible size, as a proxy for head development, in crosses segregating CBA and B6 mouse alleles (2). We analyzed strain specific genetic variation within two quantitative trait loci (QTL) on chromosomes 2 (25.5 Mb) and 18 (14.6 Mb) to identify potential modifier genes of Otx2. PhyloP scores were assigned to the SNPs on the 411 genes in the two regions. We identified 32 candidate genes, 28 genes on chromosome 2 and 4 genes on chromosome 18 that contain SNPs in evolutionarily conserved sites that differ between the two backgrounds and result in missense changes or altered splice sites. No stop, gain or loss changes were identified. Future endeavors include performing analyses of insertions, deletions, and structural variants to complete the candidate gene list. We plan to filter the complete list based on gene expression, and to select the best candidate genes for functional studies. Identifying the genes and pathways that can influence the penetrance of OTX2 haploinsufficiency phenotypes will be valuable for increasing our basic understanding of head development and for predicting patient outcomes.
1. Fang Q, George A et al., Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era. In review.
2. Hide et al., Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice. Development, 129:4347-57, 2002.