In the present study, clinical symptoms, laboratory assays, pedigree data, and genomic DNA sequence analysis were used in order to establish an odonto-HPP genotype–phenotype association, and these data are summarized in Fig. 1. Tracing the family history, the mother of the probands (subjects A and B) was asymptomatic, and her serum ALP activity was found to be normal (51 U/L; normal range 25–100 U/L). However,

the father presented clinical signs of dental abnormalities including short Everolimus roots, mild enamel defects, pulp chamber enlargement, low serum ALP levels (18 U/L; normal range 25–100 U/L), and reported a familial history of early tooth loss in his father. Overall, these findings suggested initially that the disorder was transmitted through autosomal dominant inheritance (Fig. 1). Screening for mutations in the ALPL gene revealed two genetic alterations in the probands ( Supplementary data). Firstly, there was a heterozygous substitution C→T at position 454-nt, leading to the substitution of cysteine for arginine 152 (p.R152C), an alteration previously described in this family and found in

the mother of the probands [18], [19] and [20]. The p.R152C (c.454C>T) missense mutation, associated to other mutation p.R184W (c.550C>T), has been reported previously in a case of adult HPP (p.[R152C];[R184W]; SESEP — University of Versailles- Saint Quentin), Galunisertib research buy whereas a mutation affecting the same codon p.R152H (c.455G>A) has been described in the mother of a patient with a lethal clinical form of HPP [28]. p.R152H is believed to be a TNAP polymorphism because this alteration was detected in 3 of 168 alleles (frequency of 1.8%) in subjects from a control group with metabolic bone diseases other than HPP, including osteogenesis imperfecta [29]. It is notable that p.R152H would be a conservative missense mutation

(also termed a synonymous mutation) in terms of properties of arginine and histidine, while p.R152C would be a non-conservative missense mutation. Notably, studies have indicated that some out ALPL polymorphisms, as well as compound heterozygous mutations, may play an important role in HPP severity when associated with additional ALPL mutations [15], [21] and [29]. The second alteration identified in the probands was a heterozygous gene deletion of three base pair in-frame (AAC) at positions 1318–1320-nt (c.1318_1320delAAC), leading to deletion of asparagine (Asn, N) at codon 440 (p.N440del). While the missense mutation described above was maternally inherited, the p.N440del was of paternal origin (Fig. 1). The genetic alteration 1318_1320delAAC (p.N440del) has not been reported previously for odonto-HPP or other HPP types. Clinical dental abnormalities and low serum ALP activity in the father, in addition to the shared p.N440del, strongly suggests a genotype–phenotype correlation between p.