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Skin Condition Study Uncovers Mutations in Alzheimer's-related Genes

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Individuals in at least some families affected by a skin condition called acne inversa carry mutations to genes in a pathway previously linked to early onset Alzheimer's disease, according to a study appearing online today in Science.

Through genome-wide linkage analyses of half a dozen Han Chinese families, followed by gene sequence and expression studies, a Chinese research team found ties between acne inversa (hidradenitis suppurativa) and genes coding for components of the gamma-secretase transmembrane protein complex.

Because one of these genes — the presenilin gene PSEN1 — has been tied to early onset Alzheimer's disease, the researchers explained, understanding the role of the gamma-secretase pathway in each condition could provide clues to help targeting the pathway therapeutically.

Acne inversa is condition caused by chronic inflammation of an individual's hair follicles that can lead to skin abscesses and scarring, the researchers explained. Although past studies suggest it can be inherited in an autosomal dominant manner, they added, the condition seems to be genetically heterogeneous, resulting from a range of genetic causes.

Using genome-wide linkage and haplotype analyses in six Han Chinese families containing members with acne inversa, the researchers found a region on chromosome 19 containing a possible acne inversa-associated locus.

To explore this area in more detail, they then sifted through presenilin exons and introns at this chromosome 19 locus, turning up mutations affecting PSEN1 — one of two presenilin genes implicated in studies of early onset, familial Alzheimer's disease — as well as mutations in genes coding for the gamma-secretase co-factors presenilin enhancer 2 and nicastrin.

Individuals within each acne inversa affected family shared distinct mutations not found in unaffected controls from the same ethnic background, the team noted. And their RT-PCR analyses of lymphocytes from individuals in half of the affected families supported the notion that the mutations detected likely lead to lower expression levels for these genes — changes expected to curb gamma-secretase enzyme activity in affected individuals.

"Overall, our results establish haploinsufficiency for the [gamma]-secretase component genes as the genetic basis for a subset of familial [acne inversa] … making [gamma]-secretase a promising target for anti-[acne inversa] therapeutic drug development," co-corresponding author Xue Zhang, a researcher affiliated with the Chinese Academy of Medical Sciences & Peking Union Medical College and the China Medical University in Shenyang, and co-authors wrote.

Still, the researchers noted, even though more than a dozen of the acne inversa study participants were over the age of 50 years old, none had documented Alzheimer's or dementia symptoms, hinting that the Alzheimer's and acne inversa might crop up as a consequence of different gamma-secretase-related processes.

"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 team concluded.

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