2024-03-19T08:23:10Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1242532021-11-22T13:07:52Zcom_10261_22com_10261_1col_10261_275
Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination
López-Espíndola, Daniela
Grijota Martínez, María del Carmen
Refetoff, Samuel
Bernal, Juan
Guadaño-Ferraz, Ana
Comisión Nacional de Investigación Científica y Tecnológica (Chile)
National Institutes of Health (US)
Instituto de Salud Carlos III
Centro de Investigación Biomédica en Red Enfermedades Raras (España)
Gobierno de Chile
et al.
[Context]: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serumt hyroid hormone levels. The nature of the central nervous system damage is unknown.
[Objective]: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects.
[Design]: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy.
[Methods]: Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed.
[Results]: The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed50%reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs.
[Conclusions]: The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions,andpresent from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.
This study was supported by Grant SAF2011-25608 from the Plan Nacional de IDi and the Center for Research on Rare Diseases (Centro de Investigación Biomédica en Red Enfermedades Raras), Instituto de Salud Carlos III, Madrid, Spain; Grant DK15070 from the National Institutes of Health, Bethesda, Maryland; and a grant from the Sherman Family.
D.L.-E. is recipient of a fellowship from the “Fellowship Training Program for Advanced Human Capital, Becas Chile” from the National Commission for Scientific and Technological Research, Gobierno de Chile.
Peer Reviewed
2015-11-02T10:14:55Z
2015-11-02T10:14:55Z
2014
2015-11-02T10:14:56Z
artículo
http://purl.org/coar/resource_type/c_6501
issn: 0021-972X
e-issn: 1945-7197
Journal of Clinical Endocrinology and Metabolism 99(12): E2799-E2804 (2014)
http://hdl.handle.net/10261/124253
10.1210/jc.2014-2162
http://dx.doi.org/10.13039/501100002848
http://dx.doi.org/10.13039/100000002
http://dx.doi.org/10.13039/501100004587
25222753
Sí
none
Endocrine Society