Date Published: January 26, 2017
Publisher: Public Library of Science
Author(s): Xiao Huang, Shen Shen, Dongsheng Fan, Weidong Le.
Mutations in the UBQLN2 gene, which encodes a member of the ubiquitin-like protein family (ubiquilin-2), have been identified in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (FTD). We analyzed mutations in the UBQLN2 gene in a Chinese cohort of 515 patients with sporadic ALS (sALS). A novel missense mutation (p.M392V) was detected in one sALS patient. The p.M392V mutation substitutes a highly conserved residue, has not been reported in the population databases, and previously, at the same residue, a missense mutation p.M392I was detected in two Turkey ALS patients and was considered to be pathogenic, so the M392V is a variant of uncertain significance (VOUS) for ALS. We also found a deletion mutation (p.P500_G502del), which seems to be benign. In conclusion, our data suggest that mutations in the UBQLN2 gene are rare in Chinese sALS patients.
It has been known that UBQLN2 gene is associated with amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (FTD) . Studies of ALS cohorts from different ethnic groups have been conducted to identify the pathogenicity of UBQLN2 mutations in ALS patients, and it is now recognized that UBQLN2 mutations are not a common cause of ALS [2–7].
A total of 515 patients from mainland China were recruited in the study from January 2013 to December 2014. They were diagnosed with definite, probable or lab-supported probable ALS as per El Escorial criteria, and appeared to have sALS without clinical manifestation of FTD. Patients’ clinical data and blood samples were collected during their first visit to the outpatient department, and we have access to the information for identifying a special individual participant during the study. All patients had previously been screened for mutations in known ALS genes including SOD1, FUS, TARDBP, OPTN and DCTN1. All participants provided written informed consent in this study, which was approved by the Peking University Third Hospital Ethics Committee. Age- and sex-matched individuals without neurological disease were used as controls (n = 203).
We found a missense mutation (c.1174A>G; p.M392V) of UBQLN2 in one sALS patient (2014–042) and a deletion mutation (c.1500-1508delCATAGGCCC; p.P500_G502del) in a patient with sALS (2013–368) (Fig 1). None of these two variants were found in the 489 (203+286) healthy controls, and the two residues were both in conserved domains. As for clinical information, patient 2014–042 was a 62-year-old man who presented with a 32-month history of progressive upper limb weakness. The patient was diagnosed as ALS-FAS and had an amyotrophic lateral sclerosis function rating scale-revised (ALSFRS-R) score of 46 at diagnosis. In a two years follow-up visit, the patient now has an ALSFRS-R score of 35 and shows no sign of FTLD symptoms. Patient 2013–368 was a 63-year-old man with a 20-month history of slowly progressive limb weakness and had an ALSFRS-R score of 47 at diagnosis. At the time of report, the patient has an ALSFRS-R score of 44 and showed no sign of FTLD symptoms. In addition, we also detected a silent variant in one patient and one control: c.51T>A (p.P17P) (2/718; rs371163085), which seems to be a benign polymorphism.
The missense variant we detected, p.M392V, is a novel variant of uncertain significance (VOUS), as it was predicted to be possibly damaging (by Polyphen-2) or tolerated (by SIFT). The patient’s mother died at the age of 60 while his father was still alive at the time of report, and both of them did not show signs of weakness or atrophy. It is a pity that we did not get the DNA samples of the parent’s parents to investigate the transmission of the mutation. Interestingly, in the same position, a mutation p.M392I was detected in Turkey ALS patients, and it was thought to be deleterious . However, the onset age of the patients carrying the p.M392I mutation were fairly young (14 and 16 years old) and one of them showed a special subtype of ALS: Madras-type MND. By contrast, our patient showed a typical ALS-FAS phenotype. This may be due to that different amino acid change could lead to a different phenotype. None of these two mutations were found in public SNP resources and in controls. So, according to the ACMG Standards and guidelines for the interpretation of sequence variants , the p.M392V variant is a VOUS for ALS. The mutation is located at a quite conservative region (Fig 2), so further analyses are needed to clarify the pathogenicity of the p.M392V variant of UBQLN2, for example, to test the parental samples for the variant or functional studies of the p.M392V protein.