Novel SLCO2A1 mutations cause gender-differentiated pachydermoperiostosis

Abstract

Primary hypertrophic osteoarthropathy (PHO) is a rare familial disorder with reduced penetrance for females. The genetic mutations associated with PHO have been identified in HPGD and SLCO2A1, which involved in prostaglandin E2 metabolism. Here, we report 5 PHO patients from four non-consanguineous families. Two heterozygous mutations in solute carrier organic anion transporter family member 2A1 (SLCO2A1) were identified in two brothers by whole-exome sequencing. Three heterozygous mutations and one homozygous mutation were identified in other three PHO families by Sanger sequencing. However, there was no mutation in HPGD. These findings confirmed that homozygous or compound heterozygous mutations of SLCO2A1 were the pathogenic cause of PHO. A female individual shared the same mutations in SLCO2A1 with her PHO brother but did not have any typical PHO symptoms. The influence of sex hormones on the pathogenesis of PHO and its implication were discussed.

Keywords: exome sequencing; female atypical phenotype; hormone therapeutics; primary hypertrophic osteoarthropathy; solute carrier organic anion transporter family member 2A1.

Figure 1

The pedigree chart of the four Chinese families affected by PHO and the location of the SLCO2A1 mutations. Affected PHO patients are indicated by black symbols represent, unaffected individuals are indicated by open symbols and the asymptomatic mutation carriers are indicated by half-blackened symbols. Squares and circles indicate males and females, respectively. The arrows indicate the probands in each family. P1 and P2 had a heterozygous frameshift mutation in combination with a heterozygous missense mutation, and the father (P1, 2-F) and mother (P1, 2-M) were mono heterozygous carriers; P3 had a homozygous mutation and his father (P3-F) and mother (P3-M) were both mono heterozygous carriers; P4, P5 and P6 had compound heterozygous mutations, and their fathers and mothers (P4-F; P4-M; P5, 6-M; P5, 6-M) were mono heterozygous carriers.

Figure 2

Clinical images of the affected individual: Family3, II.1-P4. The images showed the thickening and furrowing of facial skin (A) and the clubbing of fingernails and toenails (B and C). A radiograph of tibiofibula showed periosteal hyperostosis (D). A radiograph of the hands and feet showed cortical thickening and acroosteolysis (E and F). All images were published with permission from the affected individual.

Figure 3

The orthologs and modeling of the p.R561C and p.C594Y missense mutations. (A) The alignment of the SLCO2A1 with the corresponding segments in eight species is shown. Both the p.R561C and p.C594Y missense mutations occur at the highly conserved position in the SLCO2A1. Amino acids marked with column are highly conserved among all shown species. Background color illustration: transparence: non-similar; light blue: conservative; yellow: identical. (B) Model of the prostaglandin transporter (SLCO2A1, the 11th and 12th transmenbrane regions) and location of missense mutations identified in this study. The homozygous mutation p.R561C is located within the 11th transmembrane region and the heterozygous p.C594Y mutation site is located in the extracellular loop between the 11th and 12th transmenbrane regions. p.C594 here was predicted to construct a Cys-Cys Zinc-finger motif loop with a nearby cysteine (p.C587). The mutations are indicated by arrows. The model was developed according to the NCBI protein database about SLCO2A1 (NCBI: NP_005621.2). (C) Modeling of the SLCO2A1 (529–579) p.R561C mutation. Superimposition of the WT SLCO2A1 R561 (red) and R561C mutation (blue). The R561 is localized in 11th transmembrane domain. The mutation twisted the loop structure between the adjunct 2 helix near the p.561 for about 90° rightwards.

Figure 4

Clinical images of the unaffected individual: Family4, II.3-P6. The images showed no thickening and furrowing of facial skin; and the clubbing of fingernails or toenails (A, B and C). A radiograph of tibiofibula, hands and feet show no sign of periosteal hyperostosis (D, E and F). Gynecological B-ultrasound examination showed invisibility of both ovaries (G). CT screen is also hard to detect both ovaries (H). All images are published with permission from the individual.

Figure 5

Predicted model for SLCO2A1 mutation-induced premature ovarian failure. SLCO2A1 mutations lead to a high local concentration of PGE2 by the dysfunction of PG transporter. PGE2 is luteotropic and could continually maintain the high levels of luteal origin estrogen and progesterone, meanwhile, extend the lifespan of corpora luteal. However, estrogen, of luteal origin, is responsible for the suppression of follicular development and PGE2 could inhibit the frequency of ovulation. The SLCO2A1 mutations caused long-lasting inhibition of ovarian physiology cycle may induce the premature ovarian failure.