Yan Shen of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, and Xue Zhang of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, led the research. Acne inversa (aka hidradenitis suppurativa) is marked by painful skin lesions in the armpits, groin, and other sweaty areas (Revuz, 2009 ). The familial form of the disease is autosomal dominant and generally strikes in early adulthood.

To explore the genetic basis of familial acne inversa, the researchers examined six Han Chinese families with about 60 people affected across multiple generations. From a genome-wide linkage scan and haplotype analysis on two of these families, the team mapped a disease locus to a stretch of chromosome 19 containing PSENEN. This gene encodes presenilin enhancer 2 (PEN2), one of the four subunits of γ-secretase.

In subsequent sequence analysis of the six families, the scientists found heterozygous gamma-secretase mutations in all affected individuals available for study. Three mutations landed in PEN2, two affect the cofactor subunit nicastrin (NCT), and one occurs within the catalytic component presenilin 1 (PS1). Most were frameshift or nonsense mutations, and none appeared in the study’s 200 ethnically matched controls. In mRNA analysis of blood from affected family members, the researchers found sharply reduced transcript expression from the mutant allele, suggesting these are loss-of-function mutations. (In Alzheimer disease, autosomal-dominant mutations have been described for PSEN1 and 2, not in PEN2 or nicastrin.)

“The novel mutations described here are the first examples that cause complete haploinsufficiency of PSEN (the gene encoding presenilin),” Bart De Strooper, University of Leuven, Belgium, noted in an email to ARF (see full comment below). This contrasts with the PSEN mutations underlying familial Alzheimer disease (FAD), which cause only partial loss-of-function of γ-secretase (De Strooper, 2007; Wolfe, 2007), he wrote.

Because complete loss of function would lower all forms of Aβ generation, De Strooper expects that acne inversa patients would actually be protected against AD. Of the 50 patients genotyped in the current study, none showed dementia symptoms.

“If further studies confirm that familial AD and [acne inversa] are mutually exclusive phenotypes in individuals with PSEN1 mutations, then our findings suggest that PSEN1 mutations may cause familial AD and [acne inversa] through distinct mechanisms, and that simple inactivation of a single PSEN1 allele may not be sufficient to cause familial AD,” the authors write.—Esther Landhuis.

Reference:
Wang B, Yang W, Wen W, Sun J, Su B, Liu B, Ma D, Lv D, Wen Y, Qu T, Chen M, Sun M, Shen Y, Zhang X. Gamma-secretase gene mutations in familial acne inversa. Science. 7 October 2010. Abstract