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Transient neonatal diabetes mellitus type 1 (also called 6q24 in relation to an associated genetic locus) is a rare imprinted disease with symptoms of intrauterine growth retardation, hyperglycemia, and failure to thrive during the first several months of life. Hyperglycemia is treated with insulin and resolves within the first eighteen months. Molecular genetic analysis shows that it results from an overexpression of PLAG1 (Pleiomorphic Adenoma Gene-Like 1, also called ZAC) and HYMAI (Hydatidiform Mole Associated and Imprinted) found within the chromosome 6q24 locus. Pleiomorphic adenoma gene-like 1 codes for a zinc-finger protein with DNA binding activity and is thought to function in transcriptional regulation of many genes; one of which is for a ligand that functions as an autocrine hormone for beta cell development/function and others that are tumor suppressors. The other gene, HYMIA is within the PLAG1 gene body and codes for a non-translated mRNA (a long, non-coding RNA). There are three different genetic mechanisms for the disease: 1) paternal uniparental isodisomy, 2) duplication of the 6q24 on the paternal allele, and 3) hypomethylation of differentially methylated (imprinting control region) of the promoter for the PFLAG1/HYMAI genes of the maternal chromosome. From this information, answer the following questions (2 pt).
i)Which parental allele is expressed?
ii)Why is the hyperglycemia transient (resolves in 18 months or less) in diseased patients?
iii)How can you determine paternal uniparental isodisomy?
iv)Besides DNA sequence analysis, how else could you determine, at the genetic molecular level, if a patient has transient neonatal diabetes mellitus type 1 caused by paternal uniparental isodisomy (there are other types with loci on different chromosomes or in different regions of chromosome 6)?
Sample Solution
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