Could it be that a γ-secretase mutation helped give rise to communism? Research published today in Science online raises this provocative question, even just in flaky jest. Studying modern-day families with acne inversa—a rare skin disease believed to have afflicted the German philosopher Karl Marx (Shuster, 2008; see also Sunday Times story)—scientists have traced genetic underpinnings of the disorder to novel mutations in components of the γ-secretase complex.

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

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  1. This work is a strong support for the central role of Aβ peptide in the causation of familial Alzheimer’s Disease (FAD) in the PSEN families. Indeed the novel mutations described here are the first examples that cause complete haploinsufficiency of PSEN. This is in contrast to the classical FAD-PSEN mutations, which are causing partial loss of function. Complete loss of function should interfere strongly with Notch signaling, but will at the same time lower all forms of Aβ generation. I would therefore predict that such patients are actually protected against AD, and it is very exciting to read that they indeed do not show any symptoms of dementia. The skin abnormalities of these patients are, in contrast, completely compatible with loss of Notch signaling.

    The observations in this paper support Mike Wolfe’s and my proposal of some years ago that the FAD mutations cause AD by “partial loss of proteolysis function” (De Strooper, 2007; Wolfe, 2007; see also DeStrooper/Davies Live Discussion, Shen/Kelleher Live Discussion). The PSEN mutations associated with FAD have indeed a qualitative effect: they only decrease the efficiency of the γ-secretase, which results in a relative shift of the Abeta profiles to longer Aβ peptides. Therefore, and although they are also loss–of-function mutations, the PSEN-FAD mutations cause AD, while the novel acne inversa mutations, which block all Aβ generation, do not.

    It is also very significant that in the acne inversa patients, mutations were described in three of the four gamma-secretase subunits, while in FAD patients mutations are observed only in the catalytic PSEN subunit. The latter are always missense mutations, causing single amino acid substitutions in most of the cases. This indicates that partial functionality of the γ-secretase is needed to cause AD.

    In conclusion: I consider this paper as very interesting evidence in favor of the hypothesis that only partial loss-of-function mutations of PSEN1&2 can cause FAD and that they necessarily operate via changing the Aβ profiles (see Bentahir et al., 2006; De Strooper, 2007; Kuperstein et al., 2010). Deficiency of the Notch or other signaling pathways regulated by γ-secretase is thus clearly not sufficient to cause AD.

    References:

    . Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):141-6. PubMed.

    . When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):136-40. PubMed.

    . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.

    . Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):141-6. PubMed.

References

Paper Citations

  1. . The nature and consequence of Karl Marx's skin disease. Br J Dermatol. 2008 Jan;158(1):1-3. PubMed.
  2. . Hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2009 Sep;23(9):985-98. PubMed.
  3. . Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):141-6. PubMed.
  4. . When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):136-40. PubMed.
  5. . Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. PubMed.

External Citations

  1. Sunday Times story

Further Reading

Papers

  1. . The nature and consequence of Karl Marx's skin disease. Br J Dermatol. 2008 Jan;158(1):1-3. PubMed.
  2. . Hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2009 Sep;23(9):985-98. PubMed.
  3. . Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):141-6. PubMed.
  4. . When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):136-40. PubMed.
  5. . Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. PubMed.

Primary Papers

  1. . Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. PubMed.