TMEM16E is highly expressed in bone tissue and skeletal muscle and different mutations in the human TMEM16E (ANO5 or GDD1) gene are associated with the autosomal dominant bone disease gnathodiaphyseal dysplasia (GDD) or with different recessive forms of muscular dystrophy (LGMD2L, limb-girdle muscular dystrophy-2l and distal MMD3, miyoshi muscular dystrophy-3). At present, eight GDD-causing TMEM16E/Ano5 mutations have been identified leading to amino acid exchanges at six positions, while more than 70 frameshift, nonsense, insertion, deletion and aberrant splicing mutations have been reported in LGMD2L and MMD3 patients. The physiological function of TMEM16E and its role in the pathophysiology of these diseases are currently unclear. Members of the TMEM16 or anoctamin membrane protein family are involved in a variety of functions that include ion transport, phospholipid scrambling (movement of phospholipids, in particular of phosphatidylserine, between leaflets of the membrane bilayer). In particular, TMEM16A/Ano1, 16B/Ano2 and 16F/Ano6 have a clear plasma membrane localization but while TMEM16A and B work as ‘pure’ ion channels, TMEM16F shows both Ca2+-dependent ion channel and scramblase activities. Recent data suggest that also TMEM16E/Ano5, the closest relative of TMEM16F, may as well work as a phospholipid scramblase. We use patch-clamp experiments and annexin-V binding assays to address the function of human TMEM16E and the effects of mutations causing GDD and muscular dystrophy. . Our data demonstrate that TMEM16E, when overexpressed in mammalian cell lines, displays partial plasma membrane localization and gives rise to phospholipid scrambling as well as non-selective ionic currents with slow time-dependent activation at highly depolarized membrane potentials and in the presence of elevated cytosolic Ca2+ concentrations (Di Zanni et al 2018). Furthermore, TMEM16E proteins carrying the GDD-causing T513I exchange (Marconi et al 2013) show phospholipid scrambling activity and large time-dependent ion currents even at low cytosolic Ca2+ concentrations. Contrarily, the mutation associated to LGMD S555I (Savarese et al 2015), involving an amino acid located in the putative scrambling domain, causes a loss of both ionic current and scramblase activity at high intracellular Ca2+ concentrations. Our data provide the first direct demonstration of Ca2+-dependent phospholipid scrambling activity for TMEM16E wild type protein and suggest that a gain-of-function of this activity contributes to the pathophysiology of GDD in bone tissue, while a loss-of function leads to muscular dystrophy.