Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Martin R. Pollak is active.

Publication


Featured researches published by Martin R. Pollak.


Nature Genetics | 2000

Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis

Joshua M. Kaplan; Sung Han Kim; Kathryn N. North; Helmut G. Rennke; Lori Ann Correia; Hui-Qi Tong; Beverly J. Mathis; José-Carlos Rodríguez-Pérez; Philip G. Allen; Alan H. Beggs; Martin R. Pollak

Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding α-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant α-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type α-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.


Science | 2010

Association of Trypanolytic ApoL1 Variants with Kidney Disease in African-Americans

Giulio Genovese; David J. Friedman; Laurence Lecordier; Pierrick Uzureau; Barry I. Freedman; Donald W. Bowden; Carl D. Langefeld; Taras K. Oleksyk; Andrea L. Uscinski Knob; Andrea J. Bernhardy; Pamela J. Hicks; George W. Nelson; Benoit Vanhollebeke; Cheryl A. Winkler; Jeffrey B. Kopp; Etienne Pays; Martin R. Pollak

Out of Africa Kidney disease is more common in African Americans than in Americans of European descent, and genetics is likely to be a major contributing factor. Genovese et al. (p. 841, published online 15 July) now show that African Americans who carry specific sequence variants in a gene on chromosome 22 encoding apolipoprotein L-1 (APOL1) have an increased risk of developing hypertension-attributed end-stage kidney disease or focal segmental glomerulosclerosis. These variants are absent from European chromosomes. Among the functions ascribed to APOL1 is the ability to lyse and kill trypanosomes. Intriguingly, APOL1 derived from the risk alleles, but not the “wild-type” allele, killed Trypanosoma brucei rhodesiense, which causes African sleeping sickness. Genetic variants associated with kidney disease in African Americans may confer protection against trypanosomes. African Americans have higher rates of kidney disease than European Americans. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease–associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans.


Nature | 2006

Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor

Gregor B. Adams; Karissa T. Chabner; Ian R. Alley; Douglas P. Olson; Zbigniew M. Szczepiorkowski; Mark C. Poznansky; Claudine H. Kos; Martin R. Pollak; Edward M. Brown; David T. Scadden

During mammalian ontogeny, haematopoietic stem cells (HSCs) translocate from the fetal liver to the bone marrow, where haematopoiesis occurs throughout adulthood. Unique features of bone that contribute to a microenvironmental niche for stem cells might include the known high concentration of calcium ions at the HSC-enriched endosteal surface. Cells respond to extracellular ionic calcium concentrations through the seven-transmembrane-spanning calcium-sensing receptor (CaR), which we identified as being expressed on HSCs. Here we show that, through the CaR, the simple ionic mineral content of the niche may dictate the preferential localization of adult mammalian haematopoiesis in bone. Antenatal mice deficient in CaR had primitive haematopoietic cells in the circulation and spleen, whereas few were found in bone marrow. CaR-/- HSCs from fetal liver were normal in number, in proliferative and differentiative function, and in migration and homing to the bone marrow. Yet they were highly defective in localizing anatomically to the endosteal niche, behaviour that correlated with defective adhesion to the extracellular matrix protein, collagen I. CaR has a function in retaining HSCs in close physical proximity to the endosteal surface and the regulatory niche components associated with it.


Nature Genetics | 2005

TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function

Jochen Reiser; Krishna R. Polu; Clemens C. Möller; Peter Kenlan; Mehmet M. Altintas; Changli Wei; Christian Faul; Stephanie Herbert; Ivan Villegas; Carmen Avila-Casado; Mary McGee; Hikaru Sugimoto; Dennis Brown; Raghu Kalluri; Peter Mundel; Paula L. Smith; David E. Clapham; Martin R. Pollak

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.


Journal of Biological Chemistry | 1996

Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor.

Mei Bai; S. J. Quinn; Sunita Trivedi; Olga Kifor; Simon Pearce; Martin R. Pollak; Karen J. Krapcho; Steven C. Hebert; Edward M. Brown

Nearly 30 mutations have been identified to date in the coding region of the extracellular calcium-sensing receptor (CaR) that are associated with inherited human hypo- and hypercalcemic disorders. To understand the mechanisms by which the mutations alter the function of the receptor may help to discern the structure-function relationships in terms of ligand-binding and G protein coupling. In the present studies, we transiently expressed eight known CaR mutations in HEK293 cells. The effects of the mutations on extracellular calcium- and gadolinium-elicited increases in the cytosolic calcium concentration were then examined. Seven inactivating mutations, which cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, show a reduced functional activity of the receptor because they may 1) reduce its affinity for agonists; 2) prevent conversion of the receptor from a putatively immature, high mannose form into the fully glycosylated and biologically active form of the CaR, in addition to lowering its affinity for agonists; or 3) fail to couple the receptor to and/or activate its respective G protein(s). Conversely, one activating mutation, which causes a form of autosomal dominant hypocalcemia, appears to increase the affinity of the receptor for its agonists.


Journal of The American Society of Nephrology | 2011

APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy

Jeffrey B. Kopp; George W. Nelson; Karmini Sampath; Randall C. Johnson; Giulio Genovese; Ping An; David J. Friedman; William A. Briggs; Richard A. Dart; Stephen M. Korbet; Michele H. Mokrzycki; Paul L. Kimmel; Sophie Limou; Tejinder S. Ahuja; Jeffrey S. Berns; Justyna Fryc; Eric E. Simon; Michael C. Smith; Howard Trachtman; Donna M. Michel; Jeffrey R. Schelling; David Vlahov; Martin R. Pollak; Cheryl A. Winkler

Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.


Nature Genetics | 2010

Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis

Elizabeth J. Brown; Johannes Schlöndorff; Daniel J. Becker; Hiroyasu Tsukaguchi; Stephen Tonna; Andrea L Uscinski; Henry N. Higgs; Joel Henderson; Martin R. Pollak

Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified that, when mutated, lead to inherited FSGS and/or the related nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal-dominant FSGS susceptibility on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.


Journal of Clinical Investigation | 1994

Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.

Martin R. Pollak; Y H Chou; S. J. Marx; Beat Steinmann; David E. C. Cole; Maria Luisa Brandi; Socrates E. Papapoulos; Fred H. Menko; Geoffrey N. Hendy; Edward M. Brown

Neonatal severe hyperparathyroidism is a rare life-threatening disorder characterized by very high serum calcium concentrations (> 15 mg/dl). Many cases have occurred in families with familial hypocalciuric hypercalcemia, a benign condition transmitted as a dominant trait. Among several hypothesized relationships between the two syndromes is the suggestion that neonatal severe hyperparathyroidism is the homozygous form of familial hypocalciuric hypercalcemia. To test this hypothesis, we refined the map location of the gene responsible for familial hypocalciuric hypercalcemia on chromosome 3q. Analyses in 11 families defined marker loci closely linked to the gene responsible for familial hypocalciuric hypercalcemia. These loci were then analyzed in four families with parental consanguinity and offspring with neonatal severe hyperparathyroidism. Each individual who was homozygous for loci that are closely linked to the gene responsible for familial hypocalciuric hypercalcemia had neonatal severe hyperparathyroidism. The calculated odds of linkage between these disorders of > 350,000:1 (lod score = 5.56). We conclude that dosage of the gene defect accounts for these widely disparate clinical phenotypes; a single defective allele causes familial hypocalciuric hypercalcemia, while two defective alleles causes neonatal severe hyperparathyroidism.


Journal of Clinical Investigation | 2003

Mice deficient in α-actinin-4 have severe glomerular disease

Claudine H. Kos; Tu Cam Le; Sumita Sinha; Joel Henderson; Sung Han Kim; Hikaru Sugimoto; Raghu Kalluri; Robert E. Gerszten; Martin R. Pollak

Dominantly inherited mutations in ACTN4, which encodes α-actinin-4, cause a form of human focal and segmental glomerulosclerosis (FSGS). By homologous recombination in ES cells, we developed a mouse model deficient in Actn4. Mice homozygous for the targeted allele have no detectable α-actinin-4 protein expression. The number of homozygous mice observed was lower than expected under mendelian inheritance. Surviving mice homozygous for the targeted allele show progressive proteinuria, glomerular disease, and typically death by several months of age. Light microscopic analysis shows extensive glomerular disease and proteinaceous casts. Electron microscopic examination shows focal areas of podocyte foot-process effacement in young mice, and diffuse effacement and globally disrupted podocyte morphology in older mice. Despite the widespread distribution of α-actinin-4, histologic examination of mice showed abnormalities only in the kidneys. In contrast to the dominantly inherited human form of ACTN4-associated FSGS, here we show that the absence of α-actinin-4 causes a recessive form of disease in mice. Cell motility, as measured by lymphocyte chemotaxis assays, was increased in the absence of α-actinin-4. We conclude that α-actinin-4 is required for normal glomerular function. We further conclude that the nonsarcomeric forms of α-actinin (α-actinin-1 and α-actinin-4) are not functionally redundant. In addition, these genetic studies demonstrate that the nonsarcomeric α-actinin-4 is involved in the regulation of cell movement.


Journal of Clinical Investigation | 2002

NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele

Hiroyasu Tsukaguchi; Akulapalli Sudhakar; Tu Cam Le; Trang T.B. Nguyen; Jun Yao; Joshua A. Schwimmer; Asher D. Schachter; Esteban Poch; Patrícia Ferreira Abreu; Gerald B. Appel; Aparecido B. Pereira; Raghu Kalluri; Martin R. Pollak

Mutations in NPHS2, encoding podocin, have been identified in childhood onset focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease is less well defined. We studied 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary FSGS. We screened family members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for disease in nine of these families. In six families, the affected individuals were compound heterozygotes for a nonconservative R229Q amino acid substitution. This R229Q variant has an allele frequency of 3.6% in a control population. In these families, R229Q was the only mutation identified on one of the two disease-associated NPHS2 alleles. We used in vitro-translated podocin and purified nephrin to investigate the effect of R229Q on their interaction and found decreased nephrin binding to the R229Q podocin. These data suggest that this common polymorphism contributes to the development of FSGS. Chromosomes bearing the R229Q mutation share a common haplotype defining an approximately 0.2-Mb region. R229Q appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.

Collaboration


Dive into the Martin R. Pollak's collaboration.

Top Co-Authors

Avatar

Edward M. Brown

Brigham and Women's Hospital

View shared research outputs
Top Co-Authors

Avatar

David J. Friedman

Beth Israel Deaconess Medical Center

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Johannes Schlöndorff

Beth Israel Deaconess Medical Center

View shared research outputs
Top Co-Authors

Avatar

Steven C. Hebert

University of Texas at Austin

View shared research outputs
Top Co-Authors

Avatar

Christine E. Seidman

Brigham and Women's Hospital

View shared research outputs
Top Co-Authors

Avatar

Joel Henderson

Brigham and Women's Hospital

View shared research outputs
Top Co-Authors

Avatar

Astrid Weins

Brigham and Women's Hospital

View shared research outputs
Top Co-Authors

Avatar

Jeffrey B. Kopp

National Institutes of Health

View shared research outputs
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge