News Release

JCI early table of contents for Sept. 24, 2013

Peer-Reviewed Publication

JCI Journals

Hereditary spastic paraplegia development associated with changes in endoplasmic reticulum

Hereditary spastic paraplegias (HSP) are a group of hereditary diseases that result in progressive loss of motor function in the lower limbs, and mutations in many different genes have been implicated in disease progression. One common feature of HSP is the progressive degradation of the axons of cortical motor neurons; however, it is not fully understood how mutations in is so many different genes result in axonal degradation. In this issue of the Journal of Clinical Investigation, Christian Hübner and colleagues at Jena University develop a mouse model of HSP by introducing a human-associated mutation into the gene encoding receptor accessory protein 1 (REEP1). Mice with this Reep1 mutation exhibited age-dependent loss of motor function and axonal degradation in the spinal cord. The authors revealed a role for REEP1 in maintaining the shape of the endoplasmic reticulum (ER) and changes in ER structure associated with Reep1 mutations might impair ER function. In the companion commentary, Ariel Deutch and colleagues at Vanderbilt University discuss how this new mouse model will be useful for understanding the how changes in ER morphology result in HSP-associated axon loss.

TITLE: A spastic paraplegia mouse model reveals REEP1-dependent ER shaping

AUTHOR CONTACT: Christian Hübner
University Hospital Jena, Jena, UNK, DEU
Phone: 0049-3641-935500; E-mail:

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TITLE: REEPing the benefits of an animal model of hereditary spastic paraplegia

Vanderbilt University, Nashville, TN, USA
Phone: (615) 327-7090.; E-mail:

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Maintaining fluid and electrolyte balance in the kidney

Distal renal tubular acidosis (dRTA) develops in response to the loss of acid secretion by α-intercalated cells in the kidney. The inability to remove acid from the body results in low blood potassium levels (hypokalemia), dehydration, and excess calcium in the urine (hypercalcemia), which leads to urinary stone formation. Recently, patients with dRTA have been identified with genetic mutations that lead to the inactivation of proton pumps found in β-intercalated cells, which have been thought to be responsible for base-secretion in the kidney. In this issue of the Journal of Clinical Investigation, Régine Chambrey and colleagues at INSERM used a mouse model of dRTA to demonstrate that genetic loss of a proton pump in β-intercalated cells results in increased levels of prostaglandin E2 in urine, which promotes hypokalemia and hypercalcemia. Furthermore, pharmacologic inactivation of the proton pump in β-intercalated cells also resulted in increased prostaglandin E2 production and dRTA-like symptom development. In the accompanying commentary, Thomas Kleyman and colleagues at University of Pittsburg highlight how this study and others have changed the traditional view on the function of different kidney cell populations in maintaining fluid and electrolyte balance.

TITLE: Renal β-intercalated cells maintain body fluid and electrolyte balance

AUTHOR CONTACT: Regine Chambrey
INSERM UMR 970, Paris, , FRA
Phone: +33 1 56 98 81 17; E-mail:

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TITLE: Opening lines of communication in the distal nephron

AUTHOR CONTACT: Thomas Kleyman
Renal-Electrolyte Division, Pittsburgh, PA, USA
Phone: 412 647-3121; Fax: 412 648-9166; E-mail:

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Development of autoimmunity in patients with common variable immune deficiency

Common variable immune deficiency (CVID) is a genetic disease associated with enhanced susceptibility to infection, autoimmunity, and decreased antibody production. Mutations in the tumor necrosis factor receptor superfamily member TACI, are associated with CVID and autoimmunity development. Interestingly, autoimmunity develops in CVID patients with only one mutated copy of TACI, and CVID patients with two mutated TACI alleles do not develop autoimmunity. In this issue of the Journal of Clinical Investigation, Eric Meffre and colleagues at Yale University evaluated B cell activation and tolerance development in healthy individuals and CVID patients with one or two mutated copies of TACI. The authors found that CVID patients with a single altered TACI allele maintained some residual B cell responsiveness that promoted development of autoantibodies, whereas individuals with 2 mutated copies of TACI have complete impairment of B cell responses, which likely prevents autoimmunity. In the companion commentary, Antonia La Cava of the University of California Los Angeles suggests that targeting residual B cell activity in CVID patients that are heterozygous for TACI mutations may provide clinical relief.

TITLE: CVID-associated TACI mutations affect autoreactive B cell selection and activation

Yale University School of Medicine, New Haven, CT, USA
Phone: 1-203-737-4535; Fax: 1-203-785-7903; E-mail:

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TITLE: Common variable immunodeficiency: two mutations are better than one

University of California Los Angeles, Los Angeles, CA, USA
Phone: 310-267-4975; Fax: 310 206-8606; E-mail:

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A link between zinc transport and diabetes

Individuals with a mutation in the gene encoding a zinc transporter, SLC30A8 have an elevated risk of developing type 2 diabetes. Insulin granules that are released from pancreatic β cells contain high levels of zinc; however, it is not clear why individuals with mutations in the SLC30A8 zinc transporter gene are predisposed to type 2 diabetes. In this issue of the Journal of Clinical Investigation, Yoshio Fujitani and colleagues at Juntendo University investigated the role of zinc transport by SLC30A8 in β cells. They found that this zinc transporter is required for insulin clearance by the liver and secreted zinc signals to β cells to stop releasing insulin. In the accompanying commentary, Alan Attie and colleagues at the University of Wisconsin-Madison discuss the dynamic regulatory role of zinc in insulin regulation.

TITLE: The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance

AUTHOR CONTACT: Yoshio Fujitani
Juntendo University Graduate School of Medicine, Tokyo, , JPN
Phone: 81-3-5802-1579; E-mail:

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TITLE: Zinc, insulin, and the liver: a ménage à trois

University of Wisconsin-Madison, Madison, WI, USA
Phone: 608-262-1372; E-mail:

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TITLE: Dendritic epidermal T cells regulate skin antimicrobial barrier function

Department Of Immunology IMM8, La Jolla, CA, USA
Phone: 858-784-2742; Fax: 858-784-8179; E-mail:

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TITLE: A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis

Brigham & Women's Hospital/Harvard Medical School, Boston, MA, USA
Phone: 617-525-4418; E-mail: ALI9@PARTNERS.ORG

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TITLE: Glucagon regulates gluconeogenesis through KAT2B and WDR5 mediated epigenetic effects

The Salk Institute, La Jolla, CA, USA
Phone: 858-453-4100 x1394; Fax: 858-552-1546; E-mail:

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TITLE: Disruption of CEP290 microtubule/membrane binding domains causes retinal degeneration

University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Phone: 215-898-0915; Fax: 215-573-7155; E-mail:

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