Founder effect in spinal and bulbar muscular atrophy (SBMA)

Abstract

We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +/- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +/- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P < 0.0001), indicating the presence of linkage disequilibrium. There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects as well as SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.

Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia

“…13 Nevertheless, in the Japanese patients the linkage disequilibrium was not as complete as in our study, where all Nordic patients shared the same GGC repeat number. A founder effect was also suggested to be responsible for the clustering of SCA6 families in the Nordrhein-Westfalia area in Germany, where the majority of the families shared allelic characteristics of three markers around the associated gene.…”

“…DNA was extracted from EDTA blood. The primers for the microsatellites were from the GDB Polymorphism Detail, except for the CAG 3 and the GGC 13 repeats in the AR gene. The microsatellites were amplified by a standard PCR method with 50 ng of template DNA, 10 pmol of each primer, 200 µM of dNTP, 1 ϫ PCR buffer (Finnzymes), 0.1 µCi of α-32 P-dCTP and 1 U of either Taq DNA polymerase (Promega) (CAG, GGC, ALAS2, DXS8032, DXS8062, DXS339 and DXS1213) or Dynazyme DNA polymerase (Finnzymes).…”

“…12 In Japanese SBMA patients linkage disequilibrium between the CAG mutation and the intragenic GGC repeat has been found, indicating a founder effect. 13 The high prevalence of SBMA among Swedish-speaking people in the district of Vaasa in Western Finland 2 and in Northern Sweden (6 in 930 000) motivated us to search for linkage disequilibrium between the mutation and 17 microsatellite markers around the AR gene, and also to estimate the time when the SBMA mutation was introduced into Finland. Our initial studies showed that all 13 Finnish families shared identical alleles for at least five adjacent markers.…”

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

“…The diagnosis is often suspected on an electromyographic (EMG) examination performed in the routine work up of a motor neuron disease. It shows a chronic neurogenic pattern with fasciculations that extend beyond the territories affected by weakness [4]. The diminution of amplitude of the sensory action potentials, in the context of a MND, is suggestive of SBMA.…”

“…SBMA is a rare disease with an estimated incidence of 1 case over 400.000 per year [2] and a multiple founder effect across the world [3] [4]. For this reason, the prevalence of the disease in various areas can be widely different, with isolated regions, such as the Vaasa region in Western Finland, presenting with particularly elevated numbers of affected patients [5].…”