Darier disease – novel mutations in ATP2A2 and genotype–phenotype correlation

Ringpfeil, Franziska; Raus, A.; DiGiovanna, John J.; Korge, Bernhard; Harth, W.; Mazzanti, Cinzia; Uitto, Jouni; Bale, Sherri J.; Richard, Gabriele

doi:10.1034/j.1600-0625.2001.100103.x

Cited by 99 publications

(111 citation statements)

References 36 publications

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“…Although DD has been genetically linked to dominant mutations in SERCA2, the phenotypic manifestations are, surprisingly, restricted to skin. Extra-cutaneous manifestations of DD remain largely enigmatic; however, certain neurophyschiatric disorders such as schizophrenia, epilepsy, and depression have been associated with the disease, albeit with no prominent genotype-to-phenotype correlation [17,18,21]. Sporadic salivary gland abnormalities, indicated by gland obstruction and metaplastic histology, have been reported [17,22], but a lack of studies demonstrating glandular dysfunction in larger patient population fails to corroborate these findings.…”

Section: Genotype To Phenotype Perspectivementioning

confidence: 60%

“…The potential role of Ca 2+ in the growth and differentiation of epithelial cells as well as keratinocytes is recognized [3,5,30]. Interestingly, the majority of SERCA2 mutations associated with classical DD reveal a reduction in the expression and activity of the pump [15][16][17][18][19][20]. Hence, an imbalance in cellular Ca 2+ signaling is an obvious readout of DD.…”

Section: Darier's Disease and Ca 2+ Signalingmentioning

confidence: 99%

“…Since the identification of the gene responsible for DD, about 140 different mutations of SERCA2 have been evaluated with different degrees of phenotypic severity associated with the levels of expression and function of the pump. However, mutations rendering a state of SERCA2 haploinsufficiency are congruent with the classical DD phenotype [12,[15][16][17][18][19][20].…”

Section: Genetics Perspectivementioning

confidence: 99%

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Darier’s disease: a calcium-signaling perspective

Pani

Singh

2007

Cell. Mol. Life Sci.

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Ca 2+ influx evoked across the plasma membrane upon internal store depletion is essential for a myriad of cellular functions including gene expression, cell proliferation, differentiation and even apoptosis. Darier's disease (DD), an autosomal dominant inherited disorder of the skin, arising due to mutations in the isoform 2 of the sarco (endo) plasmic reticulum Ca 2+ ATPase (SERCA2), exemplifies an anomaly of Ca 2+ signaling disturbances. Owing to loss of function mutations in SERCA2, keratinocytes in DD patients have a reduced pool of endoplasmic reticulum (ER) Ca 2+ . Importantly, the status of ER Ca 2+ is critical for the activation of a class of plasma membrane Ca 2+ channels referred to as store operated Ca 2+ channels (SOCs). The widely expressed transient receptor potential (TRP) family of channels is proposed to be SOCs. In this review we discuss DD from the viewpoint of Ca 2+ signaling and present a potential role for TRPC1 in the disease pathogenesis.

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Section: Genotype To Phenotype Perspectivementioning

confidence: 60%

Section: Darier's Disease and Ca 2+ Signalingmentioning

confidence: 99%

Section: Genetics Perspectivementioning

confidence: 99%

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Darier’s disease: a calcium-signaling perspective

Pani

Singh

2007

Cell. Mol. Life Sci.

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“…Mutants in Darier's Disease-Darier's disease, a human autosomal dominant skin disorder, was shown to be caused by mutations in the SERCA2b protein (43,44), and deletions and substitutions ⌬41, ⌬42, N39D, and N39T were found in the Darier's disease pedigrees (45,46). It was indicated very recently (47) that these mutants have no Ca 2ϩ transport activity.…”

Section: Relation To All Other Mutations Found To Inhibit the E1p To mentioning

confidence: 99%

Deletions of Any Single Residues in Glu40-Ser48 Loop Connecting A Domain and the First Transmembrane Helix of Sarcoplasmic Reticulum Ca2+-ATPase Result in Almost Complete Inhibition of Conformational Transition and Hydrolysis of Phosphoenzyme Intermediate

Daiho

Yamasaki

Wang

et al. 2003

Journal of Biological Chemistry

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E1P) to ADP-insensitive EP (E2P) was almost completely or strongly inhibited. Hydrolysis of E2P formed from P i was also dramatically slowed in these deletion mutants. On the other hand, the rates of the Ca 2؉ -induced enzyme activation and subsequent E1P formation from ATP were not altered by the deletions and substitutions. The results indicate that the Glu 40 -Ser 48 loop, with its appropriate length (but not with specific residues) and with its appropriate junction to A domain, is a critical element for the E1P to E2P transition and formation of the proper structure of E2P, therefore, most likely for the large rotational movement of A domain and resulting in its association with P and N domains. Results further suggest that the loop functions to coordinate this movement of A domain and the unique motion of M1 during the E1P to E2P transition.Sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA1a) 1 is a representative member of P-type ion transporting ATPases and catalyzes Ca 2ϩ transport coupled with ATP hydrolysis (Fig. 1) (Refs. 1 and 2, and for recent reviews, see Refs. 3 and 4). In the catalytic cycle, the enzyme is activated by binding of two Ca 2ϩ ions (E2 to E1Ca 2 , steps 1 and 2) and then autophosphorylated by MgATP to form ADP-sensitive phosphoenzyme (E1P, step 3). Upon formation of this EP, the bound Ca 2ϩ ions are occluded in the transport sites. The subsequent isomeric transition to ADP-insensitive form (E2P, step 4) will result in a reduction in affinity and a change in orientation of the Ca 2ϩ binding sites, and thus a Ca 2ϩ release into lumen (step 5). Finally, hydrolysis takes place and returns the enzyme into an unphosphorylated and Ca 2ϩ -unbound form (E2, step 6). E2P can also be formed from P i in the presence of Mg 2ϩ and absence of Ca 2ϩ by reversal of its hydrolysis.The enzyme has three cytoplasmic domains (N, P, and A), which are widely separated in the Ca 2ϩ bound form (E1Ca 2 ) and associated in the Ca 2ϩ -unbound and thapsigargin-bound form (E2(TG)) (5, 6) ( Fig. 2). The modeling of tubular crystals formed with decavanadate (E2V) revealed (5) that three cytoplasmic domains gather to form a most compactly organized single headpiece in E2V. With the limited proteolysis experiments, we previously showed (7, 8) that E2V is very similar to E2P in domain organization and that E2P is the intermediate having the most compactly organized headpiece in the catalytic cycle. The results further indicated that a large rotation of A domain (by ϳ90° (5)) and its strong association with P and N domains most likely occur during the E1P to E2P transition and suggested that stabilization energy provided by intimate contacts between all three cytoplasmic domains in E2P will provide energy for moving transmembrane helices and release the bound Ca 2ϩ ions.It is thus crucial to find out structural elements essential for the A domain movement and resulting domain organization and for transmitting these changes to transmembrane helices. We have recently identified the Lys 189 -Lys 205 outermost loop of A domain as...

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“…Mutations in the SERCA2 gene (ATP2A2) and the resulting defects in the SERCA2b housekeeping isoform cause an autosomal dominant genetic skin disease, Darier disease (DD) (11,12). Over 100 mutations have been found with the DD pedigrees (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). They include many nonsense mutations, and also substitution and deletion mutations of amino acid residues.…”

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confidence: 99%

Comprehensive Analysis of Expression and Function of 51 Sarco(endo)plasmic Reticulum Ca2+-ATPase Mutants Associated with Darier Disease

Miyauchi

Daiho

Yamasaki

et al. 2006

Journal of Biological Chemistry

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We examined possible defects of sarco(endo)plasmic reticulum Ca catalyze Ca 2ϩ transport coupled with ATP hydrolysis (Fig. 1) and play an essential role in maintaining Ca 2ϩ homeostasis in the cytoplasm and endoplasmic reticulum lumen of cells (1-7). SERCAs have three cytoplasmic domains: phosphorylation (P), nucleotide binding (N), and actuator (A) and 10 transmembrane helices (M1-M10 or 11 in the SERCA2b isoform, M11). In the Ca 2ϩ transport cycle, the ATPase is activated by the binding of two Ca 2ϩ ions from the cytoplasm to the transport sites composed of M4, M5, M6, and M8 (E2 3 E1Ca 2 , step 1). Asp 351 in the P domain is then phosphorylated with MgATP to form the phosphorylated intermediate (EP) (step 2). During dephosphorylation of EP, the Ca 2ϩ ions are released into the lumen. In the detailed mechanism, the dephosphorylation process includes the conformational transition of EP associated with Ca 2ϩ release (step 3) and the subsequent hydrolysis of the acylphosphate bond (step 4).The three human SERCA genes encode SERCA isoforms (8 -10). Mutations in the SERCA2 gene (ATP2A2) and the resulting defects in the SERCA2b housekeeping isoform cause an autosomal dominant genetic skin disease, Darier disease (DD) (11,12). Over 100 mutations have been found with the DD pedigrees (11-24). They include many nonsense mutations, and also substitution and deletion mutations of amino acid residues. The mutations are located throughout the SERCA2b molecule and show no "hot spots" on the primary sequence. To understand how each of the substitution and deletion mutations affects SERCA2b protein, a limited number of mutations had been explored (9 by Ahn et al. (25), 10 by Dode et al. (23), 3 by Sato et al. (26) (a total of 20 because of overlap in Refs. 23 and 25)). To provide a comprehensive insight into the molecular basis of DD, as well as to understand the basis for each case of the DD pedigrees, it is necessary to analyze further the many unexplored substitution and deletion mutations. We therefore carried out in this study a comprehensive analysis of the expression and function of most of the DD causing substitution and deletion mutations reported, i.e. the 51 mutations shown in Fig. 2. Our results showed that most of the mutations (48 of the 51) cause severe defects in protein expression and/or Ca 2ϩ transport function. The loss of the transport function was ascribed to markedly reduced ATP hydrolysis or uncoupling from ATP hydrolysis. The remaining three mutations were exceptional in that they exhibited seemingly normal protein expression and

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Darier disease – novel mutations in ATP2A2 and genotype–phenotype correlation

Cited by 99 publications

References 36 publications

Darier’s disease: a calcium-signaling perspective

Darier’s disease: a calcium-signaling perspective

Deletions of Any Single Residues in Glu40-Ser48 Loop Connecting A Domain and the First Transmembrane Helix of Sarcoplasmic Reticulum Ca2+-ATPase Result in Almost Complete Inhibition of Conformational Transition and Hydrolysis of Phosphoenzyme Intermediate

Comprehensive Analysis of Expression and Function of 51 Sarco(endo)plasmic Reticulum Ca2+-ATPase Mutants Associated with Darier Disease

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