Genetic Diversity of the Fragile X Syndrome Gene (FMR1) in a Large Sub‐Saharan West African Population

Abstract

Fragile X-associated disorders (FAD) are caused by the expansion of a CGG trinucleotide repeat found in the 5′ untranslated region of the X-linked FMR1 gene. Although examinations of characteristics associated with repeat instability and expansion of the CGG repeat upon transmission from parent to offspring has occurred in various world populations, none has been conducted in large Sub-Saharan African populations. We have examined the FMR1 CGG repeat structure in a sample of general population males drawn from Ghana. We found that Ghanaians and African Americans have similar allele frequency distributions of CGG repeat and its flanking STR markers, DXS548 and FRAXAC1. However, the distribution of the more complex marker, FRAXAC2, is significantly different. The haplotype structure of the FMR1 locus indicated that Ghanaians share several haplotypes with African Americans and Caucasians that are associated with the expanded full mutation. In Ghanaians, the majority of repeat structures contained two AGG interruptions, however, the majority of intermediate alleles (35-49) lacked AGG interruptions. Overall, we demonstrate that allelic diversity of the FMR1 locus among Ghanaians is comparable to African Americans, but includes a minority of CGG array structures not found in other populations.

Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice

“…Both male and female PM carriers older than 50 years of age may develop FXTAS, although the incidence of FXTAS in female PM carriers is less than half of males (~40% of male PM carriers vs. 8–16% of female PM carriers develop FXTAS [9, 24, 45, 64]), primarily thought due to a protective effect of the non-expanded FMR1 gene on the second X chromosome. Premutation carriers produce elevated levels (2–10 times normal measured in lymphocytes) of PM FMR1 messenger RNA (mRNA) and normal to moderately reduced levels of FMR1 protein (FMRP) in leukocytes [4, 57, 58, 70], fibroblasts [29], and brain tissue [71]. The current hypothesis underlying the pathophysiology of FXTAS focuses on a toxic mRNA gain-of-function mechanism [28].…”

Distribution of AGG interruption patterns within nine world populations

“…The data from the 9 populations were compared with data from previously published studies including samples collected and sequenced from Quebec (11), Taiwan (40), Norway, Saami, Nenets (41), Greenland (42), African American (43), Denmark (16), Basque (44), Caucasian, Mataco, Tibet, Navajo, Borneo, Mandenka, Wolof, African American (19), Brazil (45), China, Malay, India (17), and sub-saharah West Africa (46). AGG interruption patterns were determined by mnl I digestion for samples collected from England, Hispanic American, African American, and Asian American (5), Tunisian Jews, Sephardic Jews, Ashkenazic Jews, and Arabs (18), Suriu, Mayan, Karitiana, Baka, Mbuti, and Hutterite (7).…”

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

“…Several reports indicate differences among populations in the distribution of fragile X alleles into the normal, premutation and full-mutation size classes (see, for example, Arinami et al, 1993;Barros-Núñez et al, 2008;Hofstee et al, 1994;Nanba et al, 1995;Otsuka et al, 2010;Peprah et al 2010). Asian and non-Asian populations, in particular, have been reported to exhibit substantial differences, with markedly lower frequencies of premutation-and fullmutation carriers observed in Asian populations (Arinami et al, 1993;Hofstee et al, 1994;Nanba et al, 1995;Otsuka et al, 2010).…”