Carriers of the aspartylglucosaminuria genetic mutation and chronic arthritis

Abstract

Objective: To ascertain whether being a carrier of an autosomal recessive disease, aspartylglucosaminuria (AGU), predisposes to chronic arthritis, as does AGU disease. Methods: A group of 173 unrelated patients with rheumatoid arthritis (RA) but with no family members with AGU each gave a blood sample for AGUFin major mutation DNA analysis. A group of 131 AGU carriers who were parents of patients with AGU completed a questionnaire on joint symptoms and gave a blood sample for rheumatoid factor (RF) analysis. Eight RF positive parents with prolonged joint symptoms had a rheumatological evaluation. Results: Six patients (1/28) with RA were carriers of the AGUFin major mutation, whereas the carrier frequency among Finns in general is 1/50 to 1/85. Three AGU carriers had chronic arthritis (2.3%), and 17 (13%) were RF positive; the respective percentages among Finns in general are 1.4% and 5%. Conclusion: As for AGU disease, carrier status may also predispose to chronic arthritis.A spartylglucosaminuria (AGU; McKusick 208400) is an autosomal recessive disorder of glycoprotein degradation resulting from decreased activity of aspartylglucosaminidase (EC 3.5.1.26). The disease is more common in Finns than in other populations, with 240 identified cases; however, cases have been reported in all populations. A single nucleotide change (AGUFin major) in the gene encoding aspartylglucosaminidase results in the amino acid substitution Cys163Ser which is the cause of this condition in almost all Finnish patients.1 This mutation results in misfolding of the enzyme protein, loss of its enzymatic activity, and rapid degradation in the endoplasmic reticulum. Progressive mental retardation is the main symptom, and life span is usually less than 45 years.2 Chronic arthritis is common (7% of female and 4% of male patients) in patients with AGU and is characterised by onset in childhood, seropositivity for rheumatoid factor (RF), and a deforming course.3 Population screening studies on the AGUFin major gene in Finland have shown a carrier frequency of 1 case in 50-85. [4][5][6][7] Thus, in a population of 5 million Finns, over 70 000 are estimated to be carriers of AGU.We screened for AGUFin major carriers among patients with chronic arthritis, and studied the occurrence of chronic arthritis in parents of patients with AGU, to ascertain whether AGUFin major carrier status also predisposes to chronic arthritis. PATIENTS AND METHODSWe created two study groups. The first comprised 173 consecutive unrelated patients from the Rheumatism Foundation Hospital laboratory, who had RF positive rheumatoid arthritis (RA) but no cases of AGU in the family. 8 These 38 men (age range 31-78, mean 43 years) and 135 women (age range 25-78, mean 37.5 years) received a fact sheet and a consent form, which they signed when agreeing to give a blood sample for the AGUFin major mutation DNA test in connection with other laboratory tests. 9 The patients were informed of the test result and its significance, and of the possibility of genetic counselling. We co...

Detecting Genetic Associations betweenATG5and Lupus Nephritis bytrans-eQTL

“…AGA (aspartylglucosaminidase) is a lysosomal hydrolase that participates in the degradation of glycoproteins. Like other lysosomal enzymes, the deficiency of AGA leads to lysosomal storage disorder and AGA mutation was suggested to be weakly associated with chronic arthritis [ 19 ]. Thus, whether the dysfunction of AGA is associated with susceptibility to SLE by affecting autophagy—a degradation process conducted by lysosome—should be studied.…”

Aspartylglycosaminuria: a review

“…An AGU disease carrier may have a higher risk of arthritis and their facial bones show features characteristic to AGU disease [5, 18]. Life expectancy for Finnish female patients is on the average 50 years and for men 45 years.…”

Aspartylglucosaminuria: Clinical Presentation and Potential Therapies

“…1 Furthermore, up to 7% of female and 4% of male AGU patients suffer from chronic arthritis, which begins in childhood 47 ; carriers are also predisposed to developing chronic arthritis. 48…”