Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome - PubMed (original) (raw)

Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome

Joakim Klar et al. Am J Hum Genet. 2009 Aug.

Abstract

Ichthyosis prematurity syndrome (IPS) is an autosomal-recessive disorder characterized by premature birth and neonatal asphyxia, followed by a lifelong nonscaly ichthyosis with atopic manifestations. Here we show that the gene encoding the fatty acid transport protein 4 (FATP4) is mutated in individuals with IPS. Fibroblasts derived from a patient with IPS show reduced activity of very long-chain fatty acids (VLCFA)-CoA synthetase and a specific reduction in the incorporation of VLCFA into cellular lipids. The human phenotype is consistent with Fatp4 deficiency in mice that is characterized by a severe skin phenotype, a defective permeability barrier function, and perturbed VLCFA metabolism. Our results further emphasize the importance of fatty acid metabolism for normal epidermal barrier function illustrated by deficiency of a member in the FATP family of proteins.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Key Features of IPS (A and B) Premature birth of a child with IPS showing thick, caseous, desquamating skin, particularly of the head, and respiratory complications. (C) Later, the phenotype becomes mild with a cobblestone-like surface. The pictures are published with permission from the parents. (D) Electron microscopic analysis of superficial epidermis from an IPS patient showing accumulation of curved multilamellar membranes in stratum granulosum (×7,500); the inset shows the region at a higher magnification (×30,000). (E and F) Histological analysis by hematoxylin and eosin (H&E) staining of skin from an IPS patient (E) showing thickening of the epidermis when compared to normal control (F).

Figure 2

Figure 2

Overview of FATP4 Mutations and Western Analysis (A) Positions of FATP4 mutations in IPS patients with frequencies in the Scandinavian patients. (B) Schematic overview of FATP4 functional domains; the N-terminal transmembrane region (TM), the ER localization signal (ERx; aa 47–102), and the AMP binding domain (gray; aa 103–536) containing the ATP/AMP motif involved in ATP binding and adenylate formation (ATP/AMP; aa 243–345) and the conserved FATP motif of importance for fatty acid binding (FATP; aa 500–551). The numbers below the bar correspond to residues mutated in IPS. (C) Protein blot showing FATP4 protein expression in a control individual and absent expression in a patient homozygous for p.C168X (MW: FATP4 72 kDa, GAPDH 37 kDa) with a monoclonal FATP4 antibody (Abnova, 1F4-1B10).

Figure 3

Figure 3

Analysis of Skin Biopsies Analysis of skin biopsies from a control (A, C, E) and an IPS patient homozygous for p.C168X (B, D, F). (A and B) Immunostaining with a FATP4 antibody (Abnova) shows strong expression in the normal epidermis but no expression in the patient specimen. (C and D) Nile red staining shows an even distribution of lipids in the control biopsy whereas IPS is associated with an accumulation of lipids in the stratum granulosum that coincides with the normal expression pattern of FATP4 in (A). (E and F) Staining of neutral lipids with Oil Red O shows few lipid droplets in normal skin but numerous droplets in the epidermis of the patient.

Figure 4

Figure 4

Fatty Acid Activation in Fibroblasts from a Control Individual and an IPS Patient Homozygous for p.C168X (A) Acyl-CoA synthetase activities in lysates of wild-type (filled bars) and p.C168X (open bars) fibroblasts. Activation of VLCFA and LCFA were determined with erucic acid (22:1) and palmitic acid (16:0) as substrate, respectively. (B–D) Incorporation of 3H-labeled erucic acid and palmitic acid (LCFA) into (B) cholesterol esters (CE), (C) triglycerides (TG), and (D) phospholipids (PL) of wild-type and p.C168X fibroblast. Cells were cultured in the presences of 50 μM radiolabeled fatty acids for 6 hr. Subsequently, lipid fractions were separated by TLC and the comigrating radioactivity was determined by liquid scintillation counting. Data show the mean ± standard deviation (SD) and are representative for three independent experiments done in triplicate. p values are generated with two-tailed Student's t test assuming equal variance.

References

    1. Akiyama M., Shimizu H. An update on molecular aspects of the non-syndromic ichthyoses. Exp. Dermatol. 2008;17:373–382. - PubMed
    1. Akiyama M. Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms. J. Dermatol. Sci. 2006;42:83–89. - PubMed
    1. Elias P.M., Williams M.L., Holleran W.M., Jiang Y.J., Schmuth M. Pathogenesis of permeability barrier abnormalities in the ichthyoses: Inherited disorders of lipid metabolism. J. Lipid Res. 2008;49:697–714. - PMC - PubMed
    1. Huber M., Rettler I., Bernasconi K., Frenk E., Lavrijsen S.P., Ponec M., Bon A., Lautenschlager S., Schorderet D.F., Hohl D. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science. 1995;267:525–528. - PubMed
    1. Russell L.J., DiGiovanna J.J., Rogers G.R., Steinert P.M., Hashem N., Compton J.G., Bale S.J. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat. Genet. 1995;9:279–283. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources