SEPT9 mutations and a conserved 17q25 sequence in sporadic and hereditary brachial plexus neuropathy

Abstract

Background: The clinical characteristics of sporadic brachial plexus neuropathy (S-BPN) and hereditary brachial plexus neuropathy (H-BPN) are similar. During attacks, inflammation of the brachial plexus nerves has been identified in both conditions. SEPT9 mutations (Arg88Trp, Ser93Phe, 5'UTR c.-131G>C) occur in some families with H-BPN. These mutations were not found in North American kindreds with H-BPN with a conserved 500-kilobase sequence of DNA at the 17q25 chromosomal region (where SEPT9 localizes) where a founder mutation has been suggested.

Objective: To study the 17q25 sequence and SEPT9 in S-BPN (56 individuals) and H-BPN (13 kindreds).

Methods: Allele analysis at 17q25, SEPT9 DNA sequencing, and messenger RNA analysis from lymphoblast cultures were performed.

Results: A conserved 17q25 sequence was found in 5 of 13 kindreds with H-BPN and 1 individual with S-BPN. This conserved sequence was not found in the family with a SEPT9 mutation (Arg88Trp) or in 182 control subjects. SEPT9 messenger RNA expression levels did not differ between forms of H-BPN and control subjects. No known mutations of SEPT9 were found in S-BPN.

Conclusions: Rarely, individuals with S-BPN may have the same conserved 17q25 sequence found in many North American kindreds with H-BPN. Individuals with BPN with this conserved sequence do not seem to have SEPT9 mutations or alterations of messenger RNA expression levels in lymphoblast cultures and are predicted to have the most common genetic cause in North America by a founder-effect mutation.

Figure 1

The constructed kindred of one S-BPN individual with the conserved set of alleles at 17q25 also found in our H-BPN kindreds, see Figure 3. No attacks were identified in his other family members including in his father who shared the conserved set of alleles, i.e. asymptomatic carrier (black bar).

Figure 2

One of 13 kindreds studied with hereditary brachial plexus neuropathy (H-BPN) identified with SEPT-9 mutation. Top, 5-generation kindred affected by recurrent attacks of brachial plexus neuropathy with apparent dominant inheritance. (bottom, left) Sequencing analysis identifying 262C→T transition leading to Arg88Trp. (bottom, right) Complimentary strand confirmatory pyrosequencing assay showing A and G heterozygous occurrence at base position 262, with kindred evaluation on top and possible combination below.

Figure 3

Five kindreds of 13 with H-BPN and identified with a conserved set of alleles (black bar) at 17q25 when analyzed by polymorphic markers [72GT1, 72GT2, 17S937, 17S939, GT1]. Haplotypes were generated assuming least numbers of crossovers, and prior knowledge of a disease associated set of alleles between affected families with H-BPN [9].