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

Nandhagopal, Ramachandiran; Meftah, Douja; Al-Kalbani, S; Scott, Patrick

doi:10.1111/ene.13519

Cited by 15 publications

(16 citation statements)

References 17 publications

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“…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.…”

Section: Discussionsupporting

confidence: 89%

“…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. Spasticity in the lower limbs, present in the Omani and the British kindred,22 23 was also present in the patients with HMNJ, unlike the other SIGMAR1 -associated dHMN cases.…”

Section: Discussionsupporting

confidence: 89%

“…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. Spasticity in the lower limbs, present in the Omani and the British kindred,22 23 was also present in the patients with HMNJ, unlike the other SIGMAR1 -associated dHMN cases.…”

Section: Discussionsupporting

confidence: 88%

“…In recent years, various SIGMAR1 mutations were found to be associated with the development of dHMN with or without spasticity and jALS; however the number of identified patients was low in every SIGMAR1 neuropathogenic mutation with maximum 4 patients with dHMN associated to c.151+1G>T and 6 patients with jALS to c.304G>C 17–24. We report for the first time a SIGMAR1 mutation associated with a neurodegenerative disease in a large number of patients.…”

Section: Discussionmentioning

confidence: 79%

“…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.…”

Section: Introductionmentioning

confidence: 82%

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

et al. 2019

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BackgroundDistal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ.MethodsWe used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ.ResultsA homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed.ConclusionIn conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.

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Section: Discussionsupporting

confidence: 89%