Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome

Abstract

Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase (PSS ). PSS is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS . We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

“…The c.1058A>G; (p.Gln353Arg) mutation in exon 9 was identified in three previously described patients while two new cases harbored c.794T>C; (p.Leu265Pro) and c.805C>T; (p.Pro269Ser) mutations in exon 7. The p.Leu265Pro mutation corresponds to patient 1 in this report, while patient 3 in this report has c.806C>T; (p.Pro269Leu) resulting in a different amino acid substitution at the same Pro269 position to another LMS patient reported by Sousa et al (2014). Since then, two further LMS patients have been described, with mutations in exon 7 (Tamhankar et al, 2015; Whyte et al, 2015).…”

“…Gain of function mutations in PTDSS1 underlie LMS, which is an extremely rare syndrome with only 16 sporadic cases reported in the literature between 1969 and 2015 (Lenz & Majewski, 1974; Majewski, 2000; Sousa et al, 2014; Tamhankar et al, 2015; Whyte et al, 2015). Clinical features of LMS include craniotubular hyperostosis, loose skin, progeroid appearance, marked growth failure, and moderate to severe intellectual disability.…”

“…Sousa et al (2014) identified causative heterozygous missense de novo mutations in PTDSS1 in five unrelated LMS‐affected patients. The c.1058A>G; (p.Gln353Arg) mutation in exon 9 was identified in three previously described patients while two new cases harbored c.794T>C; (p.Leu265Pro) and c.805C>T; (p.Pro269Ser) mutations in exon 7.…”

“…LMS is caused by activating de novo heterozygous mutations in PTDSS1 , encoding phosphatidylserine synthase 1 (PSS1). It is not understood at present why deregulated PSS1 activity in the endoplasmic reticulum can result in skeletal dysplasia and CL (Sousa et al, 2014). The skin abnormality is particularly striking in the three patients described here.…”

“…The skin abnormality is particularly striking in the three patients described here. One patient was initially referred to the Cutis Laxa Study Group for advice and has been briefly reported in the seminal paper describing the molecular basis of LMS (Sousa et al, 2014). The other two patients described for the first time here, are the eighth and ninth LMS patients reported with a defined PTDSS1 mutation.…”