Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome

Abstract

Objective-Distal hereditary motor neuropathy type V (dHMN-V) and Charcot-Marie-Tooth syndrome (CMT) type 2 presenting with predominant hand involvement, also known as CMT2D and Silver syndrome (SS) are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and in the glycyl-tRNA synthetase encoding (GARS) genes. Mutations in the heat-shock proteins HSPB1 and HSPB8 can cause related distal hereditary motor neuropathies (dHMN) and are considered candidates for dHMN-V, CMT2, and SS.Design-To define the frequency and distribution of mutations in the GARS, BSCL2, HSPB1 and HSPB8 genes we screened 33 unrelated sporadic and familial patients diagnosed as either dHMN-V, CMT2D or SS. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsResults-Four patients diagnosed with dHMN-Vor SS carried known heterozygous BSCL2 mutations (N88S and S90L). In one dHMN-V patient we detected a putative GARS mutation (A57V). No mutations were detected in HSPB1 and HSPB8. The diagnostic yield gained in the series of 33 probands was 12% for BSCL2 mutations and 3% for GARS mutations. In the series of unclassified dHMN and complicated HSP cases no mutations were found.Conclusions-Our data confirm that most likely only two mutations (N88S, S90L) in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. Mutations in GARS, HSPB1 and HSPB8. are not a common cause of dHMN-V, SS and CMT2D. We would therefore suggest that a genetic testing of dHMN-V and SS patients should begin with screening of exon 3 of the BSCL2 gene. Screening of the GARS gene is useful in patients with CMT2 with predominant hand involvement and dHMN-V. The rather low frequencies of BSCL2, GARS, HSPB1 and HSPB8 mutations in dHMN-V, CMT2D and SS patients strongly point to further genetic heterogeneity of these related disorders.

Charcot-Marie-Tooth type 2 and distal hereditary motor neuropathy: Clinical, neurophysiological and genetic findings from a single-centre experience

“…Furthermore mutations in HSPB8, HSPB1, GARS and BCSL2 may cause various clinical phenotypes including CMT2, dHMN or CMT2/dHMN (a predominantly motor CMT2 with slight neurophysiological and/or pathological sensory involvement) [7,31,24,1,10,11].…”

Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes

“…No exon 3 mutations were detected. A previously reported, non-pathogenic polymorphism (c.294?11 G[T) [11] was identified in 27 patients ( Table 2). This allele frequency is consistent with a previous report [11] and with our own data (minor allele frequency of c.294?11 G[T of 0.20 in 50 unrelated reference samples from unaffected individuals).…”

“…Results from previous studies, however, suggest that the c.263G[A (p.N88S) and c.269C[T (p.S90L) mutations in exon 3 are probably the only two seipin/ BSCL2 mutations associated with Silver syndrome and distal hereditary motor neuropathy type V and that, therefore, seipin/BSCL2 mutation analysis for these disorders may be restricted to exon 3 [11]. Both of these exon 3 mutations destroy a predicted N-glycosylation site of the seipin protein, which probably causes the accumulation of the misfolded mutant seipin in the endoplasmic reticulum (ER), leading to cell death as a result of ER stress [9].…”

Novel animal models of GARS-associated neuropathy by overexpression of mutant GARS using an adenoviral vector

“…Multiple GARS mutations have been identified in patients with these diseases: A57V, E71G, L129P, G240R, P244L, I280F, H418R, D500N, G526R, S581L and G598A (Christodoulou et al 1995;Ionasescu et al 1996;Sambuughin et al 1998;Antonellis et al 2003;Sivakumar et al 2005;Del Bo et al 2006;James et al 2006;Rohkamm et al 2007; Abe & Hayasaka 2009). L129P, H418R and G526R are involved only in dSMA-V and G240R, P244L and I280F are involved only in CMT2D, but E71G and D500N are involved in either CMT2D or dSMA-V (Christodoulou et al 1995;Ionasescu et al 1996;Sambuughin et al 1998;Antonellis et al 2003;Sivakumar et al 2005;Del Bo et al 2006;James et al 2006;Rohkamm et al 2007;Abe & Hayasaka 2009). Most of dSMA-V-or CMT2D-associated mutations have a range of effects on dimer interactions, whereas L129P and G240R GARS mutations have less capacity to form dimer (Nangle et al 2007).…”