Kentaro Nagamine

A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also called APS-1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is characterized by two of the three major clinical symptoms that may be present: Addison’s disease, and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. We have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes and fetal liver, and encodes a protein with two putative zinc fingers and other motifs suggestive of a transcriptional regulator. Seven mutations have been described to date, including R257X, the predominant Finnish and northern Italian APECED allele, which has also been observed in other patients of diverse origin on different haplotypes. A 13-bp deletion (1094–1106del) has also been observed in several patients of different geo-ethnic origin. The other described mutations appear to be rare. We present mutational analyses of the AIRE gene in ten Sardinian APECED families and show that there is a mutation, R139X, associated with one predominant haplotype unique to the Sardinian patients (18/20 independent alleles). The carrier frequency of R139X in Sardinia is 1.7%, giving an estimated population frequency of APECED of 1/14,400. Using linkage disequilibrium data, the estimated age of the R139X mutation is between 20 and 25 generations. A previously described 13-bp deletion was also observed on an allele of one patient. The identification of a single common Sardinian APECED mutation will facilitate its genetic diagnosis. Given the carrier frequency of R139X in the Sardinian population, AIRE may be implicated in the pathogenesis of other autoimmune diseases in the Sardinian population, particularly those affecting the endocrine system.

Mutation analyses of North American APS-1 patients

Autoimmune polyendocrinopathy syndrome type 1 (APS‐1; MIM# 240300) is a rare autosomal recessively inherited disease characterised by destructive autoimmune diseases of endocrine glands. The gene responsible for APS‐1, known as AIRE (for autoimmune regulator), was recently identified and contains motifs suggestive of a transcription regulator. To date, nine APS‐1‐associated mutations have been identified in the AIRE gene, including two common mutations R257X and 1094‐1106del. In addition to these two mutations, we report seven novel mutations in 16 APS‐1 patients from North America. We found that 1094‐1106del and R257X were the most common mutations in this population of mixed geoethnic origin, accounting for 17/32 and 4/32 alleles, respectively. Haplotype analyses suggest that both are recurrent mutations, occurring on several different haplotypes with closely linked markers. All the novel mutations appear to be rare, occurring in only single APS‐1 families. After examining all coding sequences and exon/intron boundaries of the AIRE gene, the other APS‐1 allele remained unidentified in three patients. Genotype‐phenotype correlations for APS‐1 remain difficult, suggesting that other genetic or environmental factors, or both, influence the clinical presentation and disease progression in individual APS‐1 patients. Hum Mutat 13:69–74, 1999.

APECED: A monogenic autoimmune disease providing new clues to self- tolerance

Abstract The cloning of AIRE , the gene for autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) promises to unravel some of the mysteries of autoimmunity. Here, Part Peterson and colleagues discuss recent studies of AIRE and the implications for disease therapy.

Two Cases of Unverricht-Lundborg Disease Diagnosed Using Genetic Studies

Purpose: Progressive myoclonus epilepsy type 1 (EPMl), also known as Unverricht‐Lundborg disease, is an autosomal recessive disorder characterized by stimulus‐sensitive myoclonus, tonic‐clonic seizures, and slowly progressing cerebellar signs and dementia, with onset between age 6 and 15 years. Recently a few point mutations were identified in the gene encoding cystatin B on chromosome 21q22 of patients with EPMl in Europe. We examined the gene encoding cystatin B of two unrelated Japanese patients suspected to have EPMI.