Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy

Abstract

Distal hereditary motor neuropathies represent a group of rare genetic disorders characterized by progressive distal motor weakness without sensory loss. Their genetic heterogeneity is high and thus eligible for diagnostic whole exome sequencing. The authors report successful application of whole exome sequencing in diagnosing a second consanguineous family with distal hereditary motor neuropathy due to a homozygous c.151+1G>T variant in SIGMAR1. This variant was recently proposed as causal for the same condition in a consanguineous Chinese family. Compared to this family, the Afghan ethnic origin of our patient is distinct, yet the features are identical, validating the SIGMAR1 deficiency phenotype: progressive muscle wasting/weakness in lower and upper limbs without sensory loss. Rapid disease progression during adolescent growth is similar and may be due to SIGMAR1’s role in regulating axon elongation and tau phosphorylation. Finally, the authors conclude that SIGMAR1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies.

Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation

“…Our study included individuals of one newly diagnosed HMNJ pedigree, in addition to individuals from two previously described HMNJ families. The main clinical features such as distal weakness, wasting and the pyramidal signs fading with age were similar to that of our previous report as well as to the other SIGMAR1 -associated dHMNs 7 18 20–24. Furthermore, nerve conduction studies and electromyography findings were also comparable to those observed in other SIGMAR1 -associated dHMNs and in our previous HMNJ report 7 18 20 21 23.…”

“…Recently, homozygous or compound heterozygous SIGMAR1 mutations have been implicated in the development of dHMN with pyramidal signs as well as juvenile amyotrophic lateral sclerosis (jALS), two conditions sharing several phenotypical features 17–24. Here, we present functional studies in support of a novel SIGMAR1 mutation causing HMNJ, when present in homozygosity.…”

The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

“…; Lee et al. ), with the most extensively characterized mutation being Sig‐1R‐E102Q, which results in familial ALS (Al‐Saif et al. ).…”

“…Knockout of SIGMAR1 exacerbates ALS in a SOD-1G93A mouse model by increasing neuronal excitability (Mavlyutov et al 2013), and disturbing protein and calcium homeostasis in ALS patients (Vollrath et al 2014). Gene mutations in SIG-MAR1 also result in MND (Luty et al 2010;Al-Saif et al 2011;Li et al 2015;Gregianin et al 2016;Lee et al 2016), with the most extensively characterized mutation being Sig-1R-E102Q, which results in familial ALS (Al-Saif et al 2011). Expression of Sig-1R-E102Q results in mitochondrial dysfunction (Tagashira et al 2014;Fukunaga et al 2015;Shinoda et al 2015), ER-stress-mediated disruptions in protein homeostasis (Dreser et al 2017), and inactivation of Kir2.1 potassium channels (Wong et al 2016).…”

Recessive distal motor neuropathy with pyramidal signs in an Omani kindred: underlying novel mutation in the SIGMAR1 gene

“…The typical clinical features include distal weakness and amyotrophy predominantly affecting the lower limbs more than the upper limbs with absent ankle jerks and brisk knee jerks, and absence of sensory abnormalities. Exceptions to these features included brisk ankle jerks being reported in the initial report of SIGMAR1 mutation Afghan family [6] Italian family [7] Italian family [7] Jerash (Jordanian) family [8] French-British family [9] Saudi family [10] Hispanic family [11] Genotypic feature SIGMAR1 Afghan family [6] Italian family [7] Italian family [7] Jerash (Jordanian) family [8] French-British family [9] Saudi family [10] Hispanic family [11] Overall phenotype in a Saudi family in whom the phenotypic feature was labelled as juvenile amyotrophic lateral sclerosis type 16 [10], an Italian family [7] and Hispanic kindred [11]. Lower limb spasticity was a prominent feature in the Omani male reported here and in the British [9], Saudi [10] and Hispanic [11] kindreds.…”