Clinically, the human SGNE1 DNA fragment may serve as a molecular probe of this locus in both the Prader-Willi and the Angelman syndromes, which are often accompanied by submicroscopic chromosomal deletions in the 15q11-15q13 region.
FISH analysis on a previously reported case of familial AS confirmed a submicroscopic deletion including YACs corresponding to LS6-1, TD3-21 and GABRB3 and supports the separation of the PWS and AS critical regions.
In contrast to our findings for patients with Prader-Willi syndrome, in which maternal UPD was common, our data demonstrate that paternal UPD is infrequent in patients with Angelman syndrome.
Chromosomal rearrangement breakpoints--in one Angelman syndrome (AS) patient with an unbalanced translocation and in another patient with a submicroscopic deletion--are located within the large GABRB3 intron.
Analysis of linkage of AS to GABRB3 in these three families, on the assumption of imprinted inheritance (i.e., penetrance of an AS mutation is 1 if transmitted maternally and is 0 if transmitted paternally), indicates a maximum lod score of 3.52 at theta = 0.
DNA studies in 22 families with Angelman syndrome (AS) were performed using the chromosome 15 marker loci D15S9, D15S10, D15S11, D15S12, D15S13, D15S18, D15S24, D15S86, the alpha-actin gene and the GABA beta 3 receptor gene (GABRB3).
The human P gene corresponds to the D15S12 locus within the chromosome segment 15q11-q13, which is typically deleted in patients with Prader-Willi and Angelman syndrome (see ref.5 for review).
DNA studies in 22 families with Angelman syndrome (AS) were performed using the chromosome 15 marker loci D15S9, D15S10, D15S11, D15S12, D15S13, D15S18, D15S24, D15S86, the alpha-actin gene and the GABA beta 3 receptor gene (GABRB3).
Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes.
To date, the AS critical region has been defined by an inherited deletion of approximately 1.5Mb, spanning the 3-21 (D15S10), LS6-1 (D15S113) and GABRB3 loci.
Molecular analysis of patients with varying deletions has localized the AS locus to the interval between D15S113 and GABRB3 and the PWS locus between D15S13 and D15S113.
The GABRB3/GABRA5 region appears, therefore, to be enriched for highly informative (CA)n. This set of closely spaced, short tandem repeat polymorphisms will be useful in the molecular analyses of Prader-Willi and Angelman syndromes and in high-resolution studies of genetic recombination within this region.
IPW is located about 150 kb distal to SNRPN, the only other known gene in the deletion interval, and about 50 kb proximal to the breakpoint of a translocation which defines the distal end of the PWS region and the proximal end of the Angelman syndrome (AS) region.
The ability to analyze for imprinting and expression of SNRPN and other genes in this region in cultured human cells will be a valuable tool for analyzing the molecular basis of the Prader-Willi and Angelman syndromes, although imprinting may differ between cultured cells and tissues.(ABSTRACT TRUNCATED AT 250 WORDS)