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. 2008 Dec;45(12):827-31.
doi: 10.1136/jmg.2007.057158. Epub 2008 Aug 15.

A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia

L Bonafé, J Hästbacka, A de la Chapelle, A B Campos-Xavier, C Chiesa, A Forlino, A Superti-Furga, A Rossi

A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia

L Bonafé et al. J Med Genet. 2008 Dec.

Abstract

Background: Mutations in the sulfate transporter gene SLC26A2 (DTDST) cause a continuum of skeletal dysplasia phenotypes that includes achondrogenesis type 1B (ACG1B), atelosteogenesis type 2 (AO2), diastrophic dysplasia (DTD), and recessive multiple epiphyseal dysplasia (rMED). In 1972, de la Chapelle et al reported two siblings with a lethal skeletal dysplasia, which was denoted "neonatal osseous dysplasia" and "de la Chapelle dysplasia" (DLCD). It was suggested that DLCD might be part of the SLC26A2 spectrum of phenotypes, both because of the Finnish origin of the original family and of radiographic similarities to ACG1B and AO2.

Objective: To test the hypothesis whether SLC26A2 mutations are responsible for DLCD.

Methods: We studied the DNA from the original DLCD family and from seven Finnish DTD patients in whom we had identified only one copy of IVS1+2T>C, the common Finnish mutation. A novel SLC26A2 mutation was found in all subjects, inserted by site-directed mutagenesis in a vector harbouring the SLC26A2 cDNA, and expressed in sulfate transport deficient Chinese hamster ovary (CHO) cells to measure sulfate uptake activity.

Results: We identified a hitherto undescribed SLC26A2 mutation, T512K, homozygous in the affected subjects and heterozygous in both parents and in the unaffected sister. T512K was then identified as second pathogenic allele in the seven Finnish DTD subjects. Expression studies confirmed pathogenicity.

Conclusions: DLCD is indeed allelic to the other SLC26A2 disorders. T512K is a second rare "Finnish" mutation that results in DLCD at homozygosity and in DTD when compounded with the milder, common Finnish mutation.

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Figures

Figure 1
Figure 1
Pedigree of the original family reported by de la Chapelle et al. There is pronounced consanguinity in the ancestry. Subject VIII3, whose DNA was not available (na) for this study, presented the same skeletal phenotype as subject VIII1 and VIII2.
Figure 2
Figure 2
Phenotypic features of de la Chapelle dysplasia. (A) Photograph of subject VIII1 (fig 1), a male baby born at term with weight 2750 g and length 40 cm, who died shortly after birth. There is severe micromelia, bilateral clubfoot, short fingers and toes, short trunk with protuberant abdomen, and micrognathia. (B) Radiograph of subject VIII1 (fig 1): long bones are shortened and bowed with metaphyseal flaring, with conserved major axis; the humerus is V shaped, and there is pronounced hypoplasia of the ulnae and fibulae which have a triangular shape; the spine is poorly ossified with progressive narrowing of the interpediculate distance in the lower lumbosacral region; the ilia are hypoplastic. (C) Radiograph of subject VIII2 (fig 1), a female baby, born near to term with weight 2450 g and length 37 cm: the radiographic findings are similar to those of subject VIII1, with generalised micromelia, very hypoplastic ulna and apparent absence of the fibula, small ilia and underossified spine. Reproduced from Chapelle et al, with permission of the publisher.
Figure 3
Figure 3
Sulfate uptake in sulfate transport deficient Chinese hamster ovary (CHO) cells transfected with the two SLC26A2 mutants (R492W and T512K), with wt SLC26A2 (WT), with vector alone (VECTOR), and in non-transfected cells (CRL-2245). The activity of T512K sulfate transporter overlaps with that of non-transfected cells or transfected with the vector alone, whereas R492W shows normal sulfate uptake activity. These results confirm that T512K is pathogenic and R492W is a polymorphic variant.
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