A new mutation in GJC2 associated with subclinical leukodystrophy

Abrams, Charles K.; Scherer, Steven S.; Flores‐Obando, Rafael E.; Freidin, Mona M.; Wong, Shirley; Lamantea, Eleonora; Farina, Laura; Scaioli, V.; Pareyson, Davide; Salsano, Ettore

doi:10.1007/s00415-014-7429-1

Cited by 25 publications

(23 citation statements)

References 43 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Women with GJC2 mutations were subsequently found to be more susceptible to developing secondary lymphedema after surgical intervention for breast cancer 3 . Recessive mutations in GJC2 (Cx47) have been found to cause various disorders including Pelizaeus-Merzbacher-like disease (a severe dysmyelinating disorder) 99 , hereditary spastic paraplegia 100 , and subclinical leukodystrophy 101 . Interestingly, none of these mutants developed lymphedema, which suggests that dominant negative mutations in Cx47 may be required to cause primary lymphedema, perhaps through a negative impact on Cx43 expression and/or function.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Connexin-Related Lymphedema

Castorena‐Gonzalez

Zawieja

et al. 2018

Circulation Research

View full text Add to dashboard Cite

Rationale: Mutations in GJC2 and GJA1, encoding connexins (Cxs) 47 and 43 respectively, are linked to lymphedema, but the underlying mechanisms are unknown. Because efficient lymph transport relies on the coordinated contractions of lymphatic muscle cells (LMCs) and the electrical coupling of those through Cxs, Cx-related lymphedema is proposed to result from dyssynchronous contractions of lymphatic vessels. Objective: Determine which Cx isoforms in LMCs and/or lymphatic endothelial cells (LECs) are required for the entrainment of lymphatic contraction waves and efficient lymph transport. Methods and Results: We developed novel methods to quantify the spatiotemporal entrainment of lymphatic contraction waves and used optogenetic techniques to analyze calcium signaling within and between the LMC and LEC layers. Genetic deletion of the major LEC Cxs (Cx43, Cx47, or Cx37) revealed that none were necessary for the synchronization of the global calcium events that triggered propagating contraction waves. We identified Cx45 in human and mouse LMCs as the critical Cx mediating the conduction of pacemaking signals and entrained contractions. Smooth muscle-specific Cx45 deficiency resulted in 10–18-fold reduction in conduction speed, partial-to-severe loss of contractile coordination, and impaired lymph pump function ex vivo and in vivo. Cx45-deficiency resulted in profound inhibition of lymph transport in vivo, but only under an imposed gravitational load. Conclusions: Our results: 1) identify Cx45 as the Cx isoform mediating the entrainment of the contraction waves in LMCs; 2) show that major endothelial Cxs are dispensable for the entrainment of contractions; 3) reveal a lack of coupling between LECs and LMCs, in contrast to arterioles; 4) point to lymphatic valve defects, rather than contraction dyssynchrony, as the mechanism underlying GJC2- or GJA1-related lymphedema; and 5) show that a gravitational load exacerbates lymphatic contractile defects in the intact mouse hindlimb, which is likely critical for the development of lymphedema in the adult mouse.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanisms of Connexin-Related Lymphedema

Castorena‐Gonzalez

Zawieja

et al. 2018

Circulation Research

View full text Add to dashboard Cite

show abstract

“…To the best of our knowledge, such a dissociation has only previously been reported in two sisters diagnosed with asymptomatic LBSL due to compound heterozygous mutations in DARS2 [ 12 ]. On the other hand, the dissociation between clinical and radiological phenotypes has been reported in other forms of leukodystrophies [ 13 , 14 ]. However, the biological basis of this dissociation has yet to be unraveled.…”

Section: Discussionmentioning

confidence: 99%

Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report

et al. 2018

View full text Add to dashboard Cite

BackgroundLeukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM #611105) is a genetic disease of the central nervous system characterized by lower limb spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in the DARS2 gene but has never been reported in sub-Saharan Africa so far.Case presentationTwo siblings, aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2. Sanger sequencing confirmed the presence of the mutations and their segregation in trans in both patients and in their elder sister (aged 20 years), who showed only brisk reflexes and mild lower limb spasticity. Surprisingly, in contrast to her subtle clinical presentation, the elder sister had abnormal MRI features and serum lactate levels comparable to her ill sisters.ConclusionThis report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. This may have implications for the detection of mutation carriers in LBSL.

show abstract

“…PMLD patients have severely impaired motor development, spasticity and cognitive impairment. More severe forms have been described , as well as milder forms presenting as hereditary spastic paraplegia (SPG44) .…”

Section: Gap Junction Proteinsmentioning

confidence: 99%

Genetic defects disrupting glial ion and water homeostasis in the brain

Min

Knaap

2018

Brain Pathology

View full text Add to dashboard Cite

Electrical activity of neurons in the brain, caused by the movement of ions between intracellular and extracellular compartments, is the basis of all our thoughts and actions. Maintaining the correct ionic concentration gradients is therefore crucial for brain functioning. Ion fluxes are accompanied by the displacement of osmotically obliged water. Since even minor brain swelling leads to severe brain damage and even death, brain ion and water movement has to be tightly regulated. Glial cells, in particular astrocytes, play a key role in ion and water homeostasis. They are endowed with specific channels, pumps and carriers to regulate ion and water flow. Glial cells form a large panglial syncytium to aid the uptake and dispersal of ions and water, and make extensive contacts with brain fluid barriers for disposal of excess ions and water. Genetic defects in glial proteins involved in ion and water homeostasis disrupt brain functioning, thereby leading to neurological diseases. Since white matter edema is often a hallmark disease feature, many of these diseases are characterized as leukodystrophies. In this review we summarize our current understanding of inherited glial diseases characterized by disturbed brain ion and water homeostasis by integrating findings from MRI, genetics, neuropathology and animal models for disease. We discuss how mutations in different glial proteins lead to disease, and highlight the similarities and differences between these diseases. To come to effective therapies for this group of diseases, a better mechanistic understanding of how glial cells shape ion and water movement in the brain is crucial.

show abstract

A new mutation in GJC2 associated with subclinical leukodystrophy

Cited by 25 publications

References 43 publications

Mechanisms of Connexin-Related Lymphedema

Mechanisms of Connexin-Related Lymphedema

Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report

Genetic defects disrupting glial ion and water homeostasis in the brain

Contact Info

Product

Resources

About