Disease relevance of Uniparental Disomy

• Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa [1].
• We report a patient with PTH-resistant hypocalcemia and hyperphosphatemia but without evidence for Albright hereditary osteodystrophy who has paternal uniparental isodisomy of chromosome 20q and lacks the maternal-specific methylation pattern within GNAS1 [2].
• Molecular genetic investigation of a female infant with Beckwith-Wiedemann syndrome (BWS) showed loss of IGF2 imprinting but no evidence of uniparental disomy [3].
• Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations [4].
• RESULTS: A patient with transient neonatal diabetes mellitus (TND) and macroglossia carrying paternal uniparental isodisomy (UPD) of chromosome 6 has been identified [5].

High impact information on Uniparental Disomy

• SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in approximately 10% of affected individuals [6].
• Because attempts to identify any novel maternally expressed transcripts were unsuccessful and because the UBE3A gene remained within a narrowed AS critical region, we searched for mutations in UBE3A in 11 AS patients without known molecular defects (large deletion, uniparental disomy, or imprinting mutation) [7].
• Documentation of maternal uniparental disomy of chromosome 7 in 10% of patients with Russell-Silver syndrome (RSS), characterized by prenatal and postnatal growth retardation and dysmorphic features, has suggested the presence of an imprinted gene on chromosome 7 whose mutation is responsible for the RSS phenotype [8].
• The use of 17 partly or fully informative microsatellite markers spanning the entire chromosome 1 revealed that the patient had both maternal uniparental meroisodisomy of a 35-cM region on 1q containing the maternal LAMB3 mutation and maternal uniparental heterodisomy of other regions of chromosome 1 [1].
• Uniparental disomy occurs infrequently in Wilms tumor patients [9].

Chemical compound and disease context of Uniparental Disomy

• Long-acting gonadotropin-releasing hormone analogue treatment for central precocious puberty in maternal uniparental disomy chromosome 14 [10].

Biological context of Uniparental Disomy

• The severe phenotype in one patient can be explained by the absence of XIST expression, the relatively large amount of Xp material in the ring and, possibly, the concomitant maternal uniparental isodisomy [11].
• Using restriction digests with the methyl-sensitive enzymes HpaII and HhaI and probing Southern blots with several genomic and cDNA probes, we have systematically scanned segments of 15q11-q13 for DNA methylation differences between patients with PWS (20 deletion, 20 uniparental disomy) and those with AS (26 deletion, 1 uniparental disomy) [12].
• The results suggest that the long-arms of the two X chromosomes are identical, i.e., uniparental isodisomy at least for Xq, and carry the same mutations in the androgen receptor gene [13].
• Paternal uniparental heterodisomy with partial isodisomy of chromosome 1 in a patient with retinitis pigmentosa without hearing loss and a missense mutation in the Usher syndrome type II gene USH2A [14].
• These include maternal deletion, paternal uniparental disomy, imprinting defects, and point mutations or small deletions within the UBE3A gene, which lies within this region [15].

Anatomical context of Uniparental Disomy

• Biallelic expression in blood is supported by the demonstration of gamma 2-COP transcripts in lymphoblastoid cell lines with maternal uniparental disomy 7 [16].
• The pattern of inheritance of TNDM and its association with chromosome 6 uniparental disomy is consistent with the presence on chromosome 6 of an imprinted gene involved in pancreatic beta-cell development [17].

Associations of Uniparental Disomy with chemical compounds

• Uniparental disomy in steroid 5alpha-reductase 2 deficiency [18].
• Maternal uniparental heterodisomy for chromosome 2: detection through 'atypical' maternal AFP/hCG levels, with an update on a previous case [19].
• AS-specific DNA methylation is found in patients carrying 3-4 Mb deletions ( approximately 70%), paternal uniparental disomy (3-5%) or imprinting center mutations (2-9%), while normal methylation pattern with biparental inheritance characterizes the remaining approximately 20-25% AS patients (Stalker et al.,1998; Tsai et al.,1998) [20].

Gene context of Uniparental Disomy

• In the human, it has been reported that the maternal uniparental disomy 7 is responsible for the Silver-Russell syndrome (SRS) whose effects include pre- and postnatal growth retardation and other dysmorphologies [21].
• In this study of 125 BWS cases, we confirm the association of tumors with constitutional defects in the 11p15 telomeric domain; six of 21 BWS cases with uniparental disomy (UPD) of 11p15 developed tumors and one of three of the rare BWS subtype with hypermethylation of the H19 gene developed tumors [22].
• Testing for paternal uniparental disomy (UPD) at 11p15.5, CDKN1C mutations, and imprinting defects at KvDMR1 was performed for 96, 32, and 47 patients, respectively [23].
• The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated [24].
• In 11 of the 56 informative cases, demethylation of KvDMR1 was related to 11p15 uniparental disomy (UPD) (nine CBWS and two IBWS) [25].

Analytical, diagnostic and therapeutic context of Uniparental Disomy

• The amplitude of the P300 component was considerably smaller in the uniparental disomy group than in the deletion and control groups [26].
• Through the methylation analysis of the SNRPN gene, microsatellite studies of loci mapped within and outside the PWS/AS region, and fluorescence in situ hybridization (FISH) study, we confirmed the diagnosis in 35 patients: 27 with a paternal deletion, and 8 with maternal uniparental disomy (UPD) [27].

References