© 2008 American Thoracic Society
A New Missense Mutation in the CASR Gene in Familial Interstitial Lung Disease with Hypocalciuric Hypercalcemia and Defective Granulocyte FunctionTo the Editor:In their article, Dr. Yang and colleagues described significant genetic differences between familial and sporadic interstitial pneumonias (1). In addition, genetic variations may be expected between the different forms of familial interstitial lung diseases (ILDs), but these remain largely unknown. In 1985, we described the inherited association of ILD, hypocalciuric hypercalcemia (HH), and defective granulocyte function in 43 members of one family (2). The common lung histologic pattern in the three probands was that of a granulomatous disease with aggregates of conchoid bodies surrounded by multinucleated giant cells (2). Auwerx and colleagues (3) showed also that the abnormalities in the calcium homeostasis were similar to those described by Marx and colleagues in benign familial HH (4). We attributed this association of ILD, HH, and defective granulocyte function (2, 3) to an autosomal, dominant inheritance pattern with a variable penetrance of the different abnormalities. Conventional chromosomal analysis did not show abnormalities. We were recently able to demonstrate that the one still living proband (male, °1929, patient 2 in Reference 2), who now has respiratory compromise with frequent respiratory infections and persisting hypercalcemia (between 11.7 and 12.2 mg/dl), is heterozygote for a missense mutation c.623G>C in exon 4 of the calcium-sensing receptor (CASR) gene, and this substitution predicts the replacement of tryptophan by serine at amino acid position 208 (p.Trp208Ser). Trp208 is located in the extracellular calcium binding domain of the receptor and is phylogenetically very strongly preserved in many species. A mutation at this position is thus likely to be pathogenic. It is conceivable that this substitution hampers the normal function of the receptor. Indeed, although Trp and Ser both are neutral polar amino acids, the substitution may cause a sterical hindrance because Trp is markedly larger than Ser. Our finding was based on PCR amplification and DNA sequence analysis of the six coding exons and part of the flanking introns of the CASR gene, using the primers described in Reference 5. The analysis used detects probably more than 99% of the mutations in the CASR gene. This mutation very likely causes the HH in this familial disorder. The mutation has not been described previously, although numerous other mutations in the CASR gene have been found in benign familial HH and in neonatal hyperparathyroidism (5) (see also www.casrdb.mcgill.ca). The intriguing question remains, however, what the relationship is between this substitution in the CASR gene and the associated ILD and defective granulocyte function.
Katholieke Universiteit Leuven
Vrije Universiteit Brussels
Katholieke Universiteit Leuven Acknowledgments The support of the Broere Charitable Foundation is acknowledged. FOOTNOTES Conflict of Interest Statement: M.D. served on advisory boards of Zambon (until 2005), Intermune (since 2006), and Boehringer Ingelheim (since 2007). W.L. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.W. was (co-)investigator for studies of Intermune, Centocor, Actelion, and Boehringer Ingelheim. G.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.T. serves as a consultant for Intermune. R.B. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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