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Manfred W Kilimann - One of the best experts on this subject based on the ideXlab platform.
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severe phenotype of phosphorylase kinase deficient liver glycogenosis with mutations in the phkg2 gene
Pediatric Research, 2003Co-Authors: Barbara Burwinkel, Manfred W Kilimann, Terje Rootwelt, E A Kvittingen, Pranesh ChakrabortyAbstract:Phosphorylase kinase-deficient liver glycogenosis manifests in infancy with hepatomegaly, growth retardation, and elevated plasma aminotransferases and lipids. It can be caused by mutations in three different genes of phosphorylase kinase subunits: PHKA2, PHKB, and PHKG2. It is usually a benign condition, often with complete resolution of symptoms during puberty. A minority of patients displays a more severe phenotype with symptomatic fasting hypoglycemia and abnormal liver histology that may progress to cirrhosis. Three patients with liver cirrhosis in childhood analyzed previously all had PHKG2 mutations. This suggested that this genotype may generally cause a more severe clinical manifestation, but to date PHKG2 mutations have been identified in only seven patients. Here, we report mutation analysis in three new patients with liver phosphorylase kinase deficiency and recurrent hypoglycemia, liver fibrosis, and lack of glucagon response but no overt cirrhosis. In all three patients, PHKG2 mutations were found (H89fs[insC], E157K, D215N, W300X). Three of these mutations are novel, bringing the total number of distinct human PHKG2 mutations to 11, found in 10 patients. We conclude that liver phosphorylase kinase deficiency with a severe phenotype, with or without cirrhosis, is indeed often caused by PHKG2 mutations. These patients require active measures to maintain normoglycemia (raw cornstarch, nocturnal tube feeding), which may also alleviate growth retardation and the development of abnormal liver histology.
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Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases
European Journal of Human Genetics, 2003Co-Authors: Barbara Burwinkel, Yoon S Shin, Paula R Clemens, Bin Hu, Anja Schroers, Shimon W Moses, Dieter Pongratz, Matthias Vorgerd, Manfred W KilimannAbstract:Muscle-specific deficiency of phosphorylase kinase (Phk) causes glycogen storage disease, clinically manifesting in exercise intolerance with early fatiguability, pain, cramps and occasionally myoglobinuria. In two patients and in a mouse mutant with muscle Phk deficiency, mutations were previously found in the muscle isoform of the Phk α subunit, encoded by the X-chromosomal PHKA1 gene (MIM # 311870). No mutations have been identified in the muscle isoform of the Phk γ subunit ( PHKG1 ). In the present study, we determined Q1the structure of the PHKG1 gene and characterized its relationship to several pseudogenes. In six patients with adult- or juvenile-onset muscle glycogenosis and low Phk activity, we then searched for mutations in eight candidate genes. The coding sequences of all six genes that contribute to Phk in muscle were analysed: PHKA1, PHKB, PHKG1 , CALM1, CALM2 and CALM3 . We also analysed the genes of the muscle isoform of glycogen phosphorylase ( PYGM ), of a muscle-specific regulatory subunit of the AMP-dependent protein kinase ( PRKAG3 ), and the promoter regions of PHKA1 , PHKB and PHKG1 . Only in one male patient did we find a PHKA1 missense mutation (D299V) that explains the enzyme deficiency. Two patients were heterozygous for single amino-acid replacements in PHKB that are of unclear significance (Q657K and Y770C). No sequence abnormalities were found in the other three patients. If these results can be generalized, only a fraction of cases with muscle glycogenosis and a biochemical diagnosis of low Phk activity are caused by coding, splice-site or promoter mutations in PHKA1, PHKG1 or other Phk subunit genes. Most patients with this diagnosis probably are affected either by elusive mutations of Phk subunit genes or by defects in other, unidentified genes.
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phosphorylase kinase deficient liver glycogenosis progression to cirrhosis in infancy associated with phkg2 mutations h144y and l225r
Journal of Medical Genetics, 2000Co-Authors: Barbara Burwinkel, M S Tanner, Manfred W KilimannAbstract:Editor—Deficiency of phosphorylase kinase (Phk), a regulatory protein kinase in glycogen metabolism, is the most frequent cause of hepatic glycogen storage disease (GSD). Patients typically present as infants with hepatomegaly, growth retardation, and raised triglycerides, cholesterol, and transaminases. Compared to other types of liver GSD, the condition is usually mild and its course is benign such that patients may even become asymptomatic as they grow up. Hypoglycaemia and lactic acidosis, for example, are uncommon in Phk deficiency in contrast to glucose-6-phosphatase deficiency (GSD type I). Hepatic architecture typically remains normal, unlike GSD III (debranching enzyme deficiency) in which hepatic fibrosis is common, and unlike GSD IV (branching enzyme deficiency) which usually progresses to cirrhosis in infancy. Only two infants with Phk deficiency and cirrhosis have been reported. Development of fibrosis and even cirrhosis was found in five older Japanese patients, but it remains to be clarified whether this observation can be generalised and also applies to other ethnic groups.1-5 Phk is a complex enzyme consisting of four different subunits, (αβγδ)4, and isoforms or splice variants exist for each subunit. This gives rise to genetic and phenotypic heterogeneity of Phk deficiency.6 A muscle specific form of Phk deficiency is caused by mutations in the gene for the muscle isoform of the α subunit, PHKA1 , which resides on the long arm of the X chromosome, whereas liver Phk deficiency can be caused by mutations in three genes: PHKA2 …
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a mutation in glut2 not in phosphorylase kinase subunits in hepato renal glycogenosis with fanconi syndrome and low phosphorylase kinase activity
Human Genetics, 1999Co-Authors: Barbara Burwinkel, Sami A Sanjad, Essam Alsabban, Abbas Alabbad, Manfred W KilimannAbstract:Fanconi-Bickel syndrome is characterized by hepato-renal glycogenosis with severe renal tubular dysfunction and rickets. It has recently been found to be associated with GLUT2 mutations in three families. In another family, low activities of liver phosphorylase kinase (Phk) have been observed, suggesting that Fanconi-Bickel syndrome might be genetically heterogeneous. We have analyzed this family for mutations in the GLUT2 gene and in the three Phk subunit genes that can cause liver glycogenosis (PHKA2, PHKB, and PHKG2). The coding sequences of all three Phk genes are normal but we have identified a homozygous missense mutation (Pro417Leu) in GLUT2. The affected proline residue is completely conserved in all mammalian glucose permease isoforms and even in bacterial sugar transporters and is believed to be critical for the passage of glucose through the permease. Seven affected individuals from different branches of the same large consanguineous sibship all are homozygous for this mutation. These findings indicate that there is no specific subtype of genetic Phk deficiency giving rise to hepato-renal glycogenosis. Rather, they provide further evidence that Fanconi-Bickel syndrome is caused by GLUT2 mutations. The low Phk activity is probably a secondary phenomenon that contributes to the deposition of glycogen in response to the intracellular glucose retention caused by GLUT2 deficiency.
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variability of biochemical and clinical phenotype in x linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene
Human Genetics, 1998Co-Authors: Barbara Burwinkel, Lluis Amat, George R F Gray, Nobutake Matsuo, Koji Muroya, Kuniaki Narisawa, Ronald J Sokol, M A Vilaseca, Manfred W KilimannAbstract:X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk α subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.
Barbara Burwinkel - One of the best experts on this subject based on the ideXlab platform.
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severe phenotype of phosphorylase kinase deficient liver glycogenosis with mutations in the phkg2 gene
Pediatric Research, 2003Co-Authors: Barbara Burwinkel, Manfred W Kilimann, Terje Rootwelt, E A Kvittingen, Pranesh ChakrabortyAbstract:Phosphorylase kinase-deficient liver glycogenosis manifests in infancy with hepatomegaly, growth retardation, and elevated plasma aminotransferases and lipids. It can be caused by mutations in three different genes of phosphorylase kinase subunits: PHKA2, PHKB, and PHKG2. It is usually a benign condition, often with complete resolution of symptoms during puberty. A minority of patients displays a more severe phenotype with symptomatic fasting hypoglycemia and abnormal liver histology that may progress to cirrhosis. Three patients with liver cirrhosis in childhood analyzed previously all had PHKG2 mutations. This suggested that this genotype may generally cause a more severe clinical manifestation, but to date PHKG2 mutations have been identified in only seven patients. Here, we report mutation analysis in three new patients with liver phosphorylase kinase deficiency and recurrent hypoglycemia, liver fibrosis, and lack of glucagon response but no overt cirrhosis. In all three patients, PHKG2 mutations were found (H89fs[insC], E157K, D215N, W300X). Three of these mutations are novel, bringing the total number of distinct human PHKG2 mutations to 11, found in 10 patients. We conclude that liver phosphorylase kinase deficiency with a severe phenotype, with or without cirrhosis, is indeed often caused by PHKG2 mutations. These patients require active measures to maintain normoglycemia (raw cornstarch, nocturnal tube feeding), which may also alleviate growth retardation and the development of abnormal liver histology.
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Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases
European Journal of Human Genetics, 2003Co-Authors: Barbara Burwinkel, Yoon S Shin, Paula R Clemens, Bin Hu, Anja Schroers, Shimon W Moses, Dieter Pongratz, Matthias Vorgerd, Manfred W KilimannAbstract:Muscle-specific deficiency of phosphorylase kinase (Phk) causes glycogen storage disease, clinically manifesting in exercise intolerance with early fatiguability, pain, cramps and occasionally myoglobinuria. In two patients and in a mouse mutant with muscle Phk deficiency, mutations were previously found in the muscle isoform of the Phk α subunit, encoded by the X-chromosomal PHKA1 gene (MIM # 311870). No mutations have been identified in the muscle isoform of the Phk γ subunit ( PHKG1 ). In the present study, we determined Q1the structure of the PHKG1 gene and characterized its relationship to several pseudogenes. In six patients with adult- or juvenile-onset muscle glycogenosis and low Phk activity, we then searched for mutations in eight candidate genes. The coding sequences of all six genes that contribute to Phk in muscle were analysed: PHKA1, PHKB, PHKG1 , CALM1, CALM2 and CALM3 . We also analysed the genes of the muscle isoform of glycogen phosphorylase ( PYGM ), of a muscle-specific regulatory subunit of the AMP-dependent protein kinase ( PRKAG3 ), and the promoter regions of PHKA1 , PHKB and PHKG1 . Only in one male patient did we find a PHKA1 missense mutation (D299V) that explains the enzyme deficiency. Two patients were heterozygous for single amino-acid replacements in PHKB that are of unclear significance (Q657K and Y770C). No sequence abnormalities were found in the other three patients. If these results can be generalized, only a fraction of cases with muscle glycogenosis and a biochemical diagnosis of low Phk activity are caused by coding, splice-site or promoter mutations in PHKA1, PHKG1 or other Phk subunit genes. Most patients with this diagnosis probably are affected either by elusive mutations of Phk subunit genes or by defects in other, unidentified genes.
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phosphorylase kinase deficient liver glycogenosis progression to cirrhosis in infancy associated with phkg2 mutations h144y and l225r
Journal of Medical Genetics, 2000Co-Authors: Barbara Burwinkel, M S Tanner, Manfred W KilimannAbstract:Editor—Deficiency of phosphorylase kinase (Phk), a regulatory protein kinase in glycogen metabolism, is the most frequent cause of hepatic glycogen storage disease (GSD). Patients typically present as infants with hepatomegaly, growth retardation, and raised triglycerides, cholesterol, and transaminases. Compared to other types of liver GSD, the condition is usually mild and its course is benign such that patients may even become asymptomatic as they grow up. Hypoglycaemia and lactic acidosis, for example, are uncommon in Phk deficiency in contrast to glucose-6-phosphatase deficiency (GSD type I). Hepatic architecture typically remains normal, unlike GSD III (debranching enzyme deficiency) in which hepatic fibrosis is common, and unlike GSD IV (branching enzyme deficiency) which usually progresses to cirrhosis in infancy. Only two infants with Phk deficiency and cirrhosis have been reported. Development of fibrosis and even cirrhosis was found in five older Japanese patients, but it remains to be clarified whether this observation can be generalised and also applies to other ethnic groups.1-5 Phk is a complex enzyme consisting of four different subunits, (αβγδ)4, and isoforms or splice variants exist for each subunit. This gives rise to genetic and phenotypic heterogeneity of Phk deficiency.6 A muscle specific form of Phk deficiency is caused by mutations in the gene for the muscle isoform of the α subunit, PHKA1 , which resides on the long arm of the X chromosome, whereas liver Phk deficiency can be caused by mutations in three genes: PHKA2 …
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a mutation in glut2 not in phosphorylase kinase subunits in hepato renal glycogenosis with fanconi syndrome and low phosphorylase kinase activity
Human Genetics, 1999Co-Authors: Barbara Burwinkel, Sami A Sanjad, Essam Alsabban, Abbas Alabbad, Manfred W KilimannAbstract:Fanconi-Bickel syndrome is characterized by hepato-renal glycogenosis with severe renal tubular dysfunction and rickets. It has recently been found to be associated with GLUT2 mutations in three families. In another family, low activities of liver phosphorylase kinase (Phk) have been observed, suggesting that Fanconi-Bickel syndrome might be genetically heterogeneous. We have analyzed this family for mutations in the GLUT2 gene and in the three Phk subunit genes that can cause liver glycogenosis (PHKA2, PHKB, and PHKG2). The coding sequences of all three Phk genes are normal but we have identified a homozygous missense mutation (Pro417Leu) in GLUT2. The affected proline residue is completely conserved in all mammalian glucose permease isoforms and even in bacterial sugar transporters and is believed to be critical for the passage of glucose through the permease. Seven affected individuals from different branches of the same large consanguineous sibship all are homozygous for this mutation. These findings indicate that there is no specific subtype of genetic Phk deficiency giving rise to hepato-renal glycogenosis. Rather, they provide further evidence that Fanconi-Bickel syndrome is caused by GLUT2 mutations. The low Phk activity is probably a secondary phenomenon that contributes to the deposition of glycogen in response to the intracellular glucose retention caused by GLUT2 deficiency.
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variability of biochemical and clinical phenotype in x linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene
Human Genetics, 1998Co-Authors: Barbara Burwinkel, Lluis Amat, George R F Gray, Nobutake Matsuo, Koji Muroya, Kuniaki Narisawa, Ronald J Sokol, M A Vilaseca, Manfred W KilimannAbstract:X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk α subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.
Patrick Willems - One of the best experts on this subject based on the ideXlab platform.
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x linked liver glycogenosis type ii xlg ii is caused by mutations in PHKA2 the gene encoding the liver α subunit of phosphorylase kinase
Human Molecular Genetics, 1996Co-Authors: Jan Hendrickx, J Fernandes, Paul Coucke, Erna Dams, Philip J Lee, Patrick WillemsAbstract:X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver α subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver α subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.
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mutations in the phosphorylase kinase gene PHKA2 are responsible for x linked liver glycogen storage disease
Human Molecular Genetics, 1995Co-Authors: Jan Hendrickx, J Fernandes, Paul Coucke, Erna Dams, Philip Lee, Michel Odievre, L Corbeel, Patrick WillemsAbstract:Phosphorylase kinase (PHK) is a key enzyme in the control of glycogen breakdown. Several types of PHK deficiency have been described of which X-linked liver glycogenosis type I (XLG I) is the most common. Since the XLG I locus and the gene encoding the liver alpha-subunit gene of PHK (PHKA2) have both been localized to Xp22, PHKA2 was a candidate gene for XLG I. In this study we identified four point mutations in four unrelated XLG I patients: three mutations introduce a premature stop codon, whereas the fourth mutation abolishes a splice site consensus sequence leading to exon skipping. These findings indicate that PHKA2 is the XLG I gene.
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cdna cloning of a liver isoform of the phosphorylase kinase alpha subunit and mapping of the gene to xp22 2 p22 1 the region of human x linked liver glycogenosis
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Jutta J Davidson, Uta Francke, Tayfun Ozcelik, Christiane Hamacher, Patrick Willems, Manfred W KilimannAbstract:We have cloned cDNA molecules encoding another isoform of the alpha subunit of phosphorylase kinase (ATP:phosphorylase-b phosphotransferase, EC 2.7.1.38). Sequence comparison with the previously characterized muscle isoform reveals a pattern of highly conserved and variable domains and demonstrates that the isoforms are the products of distinct genes. In contrast to the muscle isoform gene, PHKA1, the gene of this additional isoform, PHKA2, is predominantly expressed in liver and other nonmuscle tissues. It was mapped to the distal short arm of the human X chromosome (Xp22.2-p22.1), the same region to which human X-linked liver glycogenosis due to phosphorylase kinase deficiency has been mapped. Thus, X-linked liver glycogenosis is probably caused by mutations affecting PHKA2.
Jan Hendrickx - One of the best experts on this subject based on the ideXlab platform.
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complete genomic structure and mutational spectrum of PHKA2 in patients with x linked liver glycogenosis type i and ii
American Journal of Human Genetics, 1999Co-Authors: Jan Hendrickx, Christiane Baussan, Philip Lee, James P Keating, Dietbrand Carton, I B Sardharwalla, Mendel Tuchman, Patrick J WillemsAbstract:Summary X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-storage disease. XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver. Both types of XLG are caused by mutations in the same gene, PHKA2, that encodes the regulatory α subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic structure. The gene consists of 33 exons, spanning ⩾65 kb. By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG II, bringing the total to 19 XLG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncation or disruption of the PHKA2 protein. In contrast, all XLG II mutations are missense mutations or small in-frame deletions and insertions. These results suggest that the biochemical differences between XLG I and XLG II might be due to the different nature of the disease-causing mutations in PHKA2. XLG I mutations may lead to absence of the α subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas XLG II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.
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x linked liver glycogenosis type ii xlg ii is caused by mutations in PHKA2 the gene encoding the liver α subunit of phosphorylase kinase
Human Molecular Genetics, 1996Co-Authors: Jan Hendrickx, J Fernandes, Paul Coucke, Erna Dams, Philip J Lee, Patrick WillemsAbstract:X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver α subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver α subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.
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mutations in the phosphorylase kinase gene PHKA2 are responsible for x linked liver glycogen storage disease
Human Molecular Genetics, 1995Co-Authors: Jan Hendrickx, J Fernandes, Paul Coucke, Erna Dams, Philip Lee, Michel Odievre, L Corbeel, Patrick WillemsAbstract:Phosphorylase kinase (PHK) is a key enzyme in the control of glycogen breakdown. Several types of PHK deficiency have been described of which X-linked liver glycogenosis type I (XLG I) is the most common. Since the XLG I locus and the gene encoding the liver alpha-subunit gene of PHK (PHKA2) have both been localized to Xp22, PHKA2 was a candidate gene for XLG I. In this study we identified four point mutations in four unrelated XLG I patients: three mutations introduce a premature stop codon, whereas the fourth mutation abolishes a splice site consensus sequence leading to exon skipping. These findings indicate that PHKA2 is the XLG I gene.
Anna Keppner - One of the best experts on this subject based on the ideXlab platform.
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deletion of the serine protease cap2 tmprss4 leads to dysregulated renal water handling upon dietary potassium depletion
Scientific Reports, 2019Co-Authors: Anna Keppner, Darko Maric, Chloe Sergi, Camille Ansermet, Damien De Bellis, Denise V Kratschmar, Jeremie CanonicaAbstract:The kidney needs to adapt daily to variable dietary K+ contents via various mechanisms including diuretic, acid-base and hormonal changes that are still not fully understood. In this study, we demonstrate that following a K+-deficient diet in wildtype mice, the serine protease CAP2/Tmprss4 is upregulated in connecting tubule and cortical collecting duct and also localizes to the medulla and transitional epithelium of the papilla and minor calyx. Male CAP2/Tmprss4 knockout mice display altered water handling and urine osmolality, enhanced vasopressin response leading to upregulated adenylate cyclase 6 expression and cAMP overproduction, and subsequently greater aquaporin 2 (AQP2) and Na+-K+-2Cl− cotransporter 2 (NKCC2) expression following K+-deficient diet. Urinary acidification coincides with significantly increased H+,K+-ATPase type 2 (HKA2) mRNA and protein expression, and decreased calcium and phosphate excretion. This is accompanied by increased glucocorticoid receptor (GR) protein levels and reduced 11β-hydroxysteroid dehydrogenase 2 activity in knockout mice. Strikingly, genetic nephron-specific deletion of GR leads to the mirrored phenotype of CAP2/Tmprss4 knockouts, including increased water intake and urine output, urinary alkalinisation, downregulation of HKA2, AQP2 and NKCC2. Collectively, our data unveil a novel role of the serine protease CAP2/Tmprss4 and GR on renal water handling upon dietary K+ depletion.