Disease relevance of MKRN3

• Recent findings indicate that ZNF127 is part of the coordinately regulated imprinted domain affected in Prader-Willi syndrome patients with imprinting mutations [1].
• The ZNF127 gene encodes a protein with a RING (C3HC4) zinc-finger and multiple C3H zinc-finger motifs, the former being closely related to a protein from variola major virus, the smallpox etiological agent [1].
• The D15S9 and D15S63 loci in the Prader-Willi/Angelman syndrome region on chromosome 15 are subject to parent-of-origin-specific DNA methylation [2].

High impact information on MKRN3

• Methylation studies showed normal biparental patterns of inheritance of loci DN34/ZNF127, D15S63, and SNRPN exon 1 [3].
• To further characterize the deletion breakpoints proximal to D15S9, three new polymorphic microsatellite markers were developed that showed observed heterozygosities of 60%-87% [4].
• D15S543 was isolated from a cosmid cloned from the proximal right end of YAC 254B5 containing the D15S9 (ML34) locus [4].
• The results from this study show (a) two additional copies of proximal 15q loci, D15S9 through D15S12, in mentally retarded patients with an inv dup(15) but without AS or PWS and (b) no additional copies of these loci in patients with a normal phenotype or with PWS [5].
• We describe a complex imprinted locus in chromosome 15q11-q13 that encodes two genes, ZNF127 and ZNF127AS [1].

Biological context of MKRN3

• We have exploited this characteristic of an imprinted region by using FISH at D15S9 and SNRPN (small nuclear ribonucleo protein N) on interphase nuclei to distinguish between Angelman and Prader-Willi syndrome patient samples with uniparental disomy of chromosome 15q11-q13 (n = 11) from those with biparental inheritance (n = 13) [6].
• A BsaBI RFLP detected for probe pML34 [D15S9] on chromosome 15q [7].
• Patient studies were usually based on high resolution cytogenetic analysis, quantitative Southern blotting (with D15S9, D15S11, D15S10, D15S12 loci) and dinucleotide repeat polymorphism assay by polymerase chain reaction (PCR) (IR4 .3R and GABARB3) [8].

Other interactions of MKRN3

• Consistent with this expression pattern, in the brain the ZNF127 5' CpG island is completely unmethylated on the paternal allele but methylated on the maternal allele [1].
• By contrast, cells from the first individual expressed PAR5 and ZNF127, whereas the second expressed a single IPW allele [9].
• The distal breakpoints appear to cluster between the P gene (OCA2) and D15S24, whereas two deletion breakpoint clusters have been identified on the proximal side (one centromeric to D15S541 and one between D15S541 and D15S9) [10].
• Moreover, methylation studies of genomic imprinted loci D15S63, D15S9, and H19 have revealed hypomethylation to different degrees in both patients; this provides evidence for hypomethylation at autosomal single copy loci in ICFS [11].

Analytical, diagnostic and therapeutic context of MKRN3

• Correct prenatal diagnoses were obtained in 24 out of 24 samples using the 5' SNRPN locus; 4 out of 15 using the ZNF127 locus; and 10 out of 18 using the PW71 locus [12].

References