The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome

Abstract

Thyroid hormone is essential for the proper development and function of the brain. The active form of thyroid hormone is T(3), which binds to nuclear receptors. Recently, a transporter specific for T(3), MCT8 (monocarboxylate transporter 8) was identified. MCT8 is highly expressed in liver and brain. The gene is located in Xq13 and mutations in MCT8 are responsible for an X-linked condition, Allan-Herndon-Dudley syndrome (AHDS). This syndrome is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays. Affected males also present with muscle hypoplasia, generalized muscle weakness, and limited speech. Importantly, these patients have elevated serum levels of free T(3), low to below normal serum levels of free T(4), and levels of thyroid stimulating hormone that are within the normal range. This constellation of measurements of thyroid function enables quick screening for AHDS in males presenting with cognitive impairment, congenital hypotonia, and generalized muscle weakness.

Figure 1

(A) Schematic representation of the thyroid hormone transport and deiodination in a target cell. Both T₃ and T₄ enter the cell and are acted upon by deiodinases. The active form, T₃, enters the nucleus where it binds to a receptor that then activates the synthesis of specific messenger RNAs coding for specific proteins. D1 is predominantly expressed in liver, kidney, and thyroid; D2 is predominantly expressed in brain, anterior pituitary, skeletal muscle, and thyroid. (B) Schematic representation of the source and the transport of T₃ in the brain. T₄ enters a glial via an unknown mechanism, whereupon it is converted to T₃ by the D2 deiodinase. T₃ exits the cell via an unknown mechanism and is transported into a neuron via MCT8. Once inside the neuron, it either enters the nucleus, binding a receptor that initiates protein synthesis, or it is inactivated to T₂ by D3 deiodinase. D₁, D₂, D₃, deiodinases; RXR, retinoid X receptor;T₄, T₃ thyroid hormone; TR, thyroid hormone receptor; TRE, thyroid hormone responsive element. ? signifies that the transport/export mechanism is unknown.

Figure 1

(A) Schematic representation of the thyroid hormone transport and deiodination in a target cell. Both T₃ and T₄ enter the cell and are acted upon by deiodinases. The active form, T₃, enters the nucleus where it binds to a receptor that then activates the synthesis of specific messenger RNAs coding for specific proteins. D1 is predominantly expressed in liver, kidney, and thyroid; D2 is predominantly expressed in brain, anterior pituitary, skeletal muscle, and thyroid. (B) Schematic representation of the source and the transport of T₃ in the brain. T₄ enters a glial via an unknown mechanism, whereupon it is converted to T₃ by the D2 deiodinase. T₃ exits the cell via an unknown mechanism and is transported into a neuron via MCT8. Once inside the neuron, it either enters the nucleus, binding a receptor that initiates protein synthesis, or it is inactivated to T₂ by D3 deiodinase. D₁, D₂, D₃, deiodinases; RXR, retinoid X receptor;T₄, T₃ thyroid hormone; TR, thyroid hormone receptor; TRE, thyroid hormone responsive element. ? signifies that the transport/export mechanism is unknown.

Figure 2

(A) Genomic organization of MCT8/SLC16A2. The boxes indicate the six exons. The blue numbered areas indicate the location of the 12 transmembrane domains within the coding sequence. Location of various nonsense and missense mutations are indicated. Note the vast majority are in the transmembrane domains. ATG, transcription initiation start site; TAA, transcription stop site. (B) Structural organization of the MCT8/SLC16A2 protein. The illustration shows the 12 transmembrane domains. The two different translation start condons in the N-terminal domain are indicated by gray-shaded methionine (‘M’) residues. The currently known missense and truncating mutations are represented by various colors. Green, mutations identified by Dumitrescu et al; royal blue, mutations identified by Friesema et al and Jansen et al (unpublished data); light blue, mutations identified by Lenzer et al; red, mutations identified by Schwartz et al and Schwartz and Turner (unpublished data); brown, mutation identified by Holden et al; rose, mutation identified by Maranduba et al; turquoise, mutation identified by Herzovich et al. The F229del (F-) mutation (purple) has been observed in two unrelated families., The black circles indicate the amino acid residue that is altered. A number indicates a deletion of that many base pairs; indicates an insertion of an amino acid (3 bp); – indicates the deletion of the indicated amino acid. Modified from Figure 2 of ref .

Figure 2

(A) Genomic organization of MCT8/SLC16A2. The boxes indicate the six exons. The blue numbered areas indicate the location of the 12 transmembrane domains within the coding sequence. Location of various nonsense and missense mutations are indicated. Note the vast majority are in the transmembrane domains. ATG, transcription initiation start site; TAA, transcription stop site. (B) Structural organization of the MCT8/SLC16A2 protein. The illustration shows the 12 transmembrane domains. The two different translation start condons in the N-terminal domain are indicated by gray-shaded methionine (‘M’) residues. The currently known missense and truncating mutations are represented by various colors. Green, mutations identified by Dumitrescu et al; royal blue, mutations identified by Friesema et al and Jansen et al (unpublished data); light blue, mutations identified by Lenzer et al; red, mutations identified by Schwartz et al and Schwartz and Turner (unpublished data); brown, mutation identified by Holden et al; rose, mutation identified by Maranduba et al; turquoise, mutation identified by Herzovich et al. The F229del (F-) mutation (purple) has been observed in two unrelated families., The black circles indicate the amino acid residue that is altered. A number indicates a deletion of that many base pairs; indicates an insertion of an amino acid (3 bp); – indicates the deletion of the indicated amino acid. Modified from Figure 2 of ref .

Figure 3

Height plotted against age in 31 males with Allan--Herndon--Dudley syndrome. Open circles, eight height measurements < 3rd centile; gray circle, one height measurement > 97th centile; solid circles, specific height centiles.

Figure 4

Head circumference plotted against age in 39 males with Allan--Herndon--Dudley syndrome. Open circles, eight head circumference measurements < 3rd centile; solid circles, specific head circumference centiles.

Figure 5

VI-33 in K8005 at age 15 years (left) and 65 years (right) showing marked muscle hypoplasia.

Figure 6

Appearance of four affected males in K8225. (A) IV-1 at age 1 year, showing a normal face. (B) III-11 at age 14 years, showing an elongated and myopathic face with prominence of the eyes. (C) III-3 at age 28 years, showing synophrys and prominence of the lower lip. (D) II-8 at age 39 years, showing an elongated myopathic face with prominence of zygomatic areas and an open mouth.

Figure 6

Appearance of four affected males in K8225. (A) IV-1 at age 1 year, showing a normal face. (B) III-11 at age 14 years, showing an elongated and myopathic face with prominence of the eyes. (C) III-3 at age 28 years, showing synophrys and prominence of the lower lip. (D) II-8 at age 39 years, showing an elongated myopathic face with prominence of zygomatic areas and an open mouth.

Figure 6

Appearance of four affected males in K8225. (A) IV-1 at age 1 year, showing a normal face. (B) III-11 at age 14 years, showing an elongated and myopathic face with prominence of the eyes. (C) III-3 at age 28 years, showing synophrys and prominence of the lower lip. (D) II-8 at age 39 years, showing an elongated myopathic face with prominence of zygomatic areas and an open mouth.

Figure 6

Appearance of four affected males in K8225. (A) IV-1 at age 1 year, showing a normal face. (B) III-11 at age 14 years, showing an elongated and myopathic face with prominence of the eyes. (C) III-3 at age 28 years, showing synophrys and prominence of the lower lip. (D) II-8 at age 39 years, showing an elongated myopathic face with prominence of zygomatic areas and an open mouth.

Figure 7

Appearance of four affected males in K9248. (A) V-3 at age 22 months, showing a cupped left ear, depressed nasal bridge, and tenting of the upper lip with short philtrum. (B) V-6 at age 5 years, showing incomplete folding of superior helices and short philtrum. (C) IV-6 at age 38 years, showing elongated face with widow's peak, flattening of midface, and square jaw. (D) IV-5 at age 40 years, showing a long face with short philtrum.

Figure 7

Appearance of four affected males in K9248. (A) V-3 at age 22 months, showing a cupped left ear, depressed nasal bridge, and tenting of the upper lip with short philtrum. (B) V-6 at age 5 years, showing incomplete folding of superior helices and short philtrum. (C) IV-6 at age 38 years, showing elongated face with widow's peak, flattening of midface, and square jaw. (D) IV-5 at age 40 years, showing a long face with short philtrum.

Figure 7

Appearance of four affected males in K9248. (A) V-3 at age 22 months, showing a cupped left ear, depressed nasal bridge, and tenting of the upper lip with short philtrum. (B) V-6 at age 5 years, showing incomplete folding of superior helices and short philtrum. (C) IV-6 at age 38 years, showing elongated face with widow's peak, flattening of midface, and square jaw. (D) IV-5 at age 40 years, showing a long face with short philtrum.

Figure 7

Appearance of four affected males in K9248. (A) V-3 at age 22 months, showing a cupped left ear, depressed nasal bridge, and tenting of the upper lip with short philtrum. (B) V-6 at age 5 years, showing incomplete folding of superior helices and short philtrum. (C) IV-6 at age 38 years, showing elongated face with widow's peak, flattening of midface, and square jaw. (D) IV-5 at age 40 years, showing a long face with short philtrum.

Figure 8

IQ measurements (Stanford--Binet) plotted against age in 26 males with Allan--Herndon--Dudley syndrome. Open circles, nine IQ measurements < 20; gray circles, two IQ measurements < 30; solid circles, specific IQ values.