Jos Jansen

48 Chapter 2 has been described as the human homolog of Vma21p.(32,33) Individuals with TMEM199 deficiency showed partial clinical and biochemical overlap with CCDC115-deficient individuals, although symptoms seem to be milder. TMEM199-deficient individuals presented in adolescence with a phenotype of elevated ATs and ALP, hypercholesterolemia, hepatic steatosis, and low ceruloplasmin. Profound hepatosplenomegaly and PMD, as seen in CCDC115 deficiency, were absent. Compared to known V-ATPase associated disorders, CCDC115 deficiency (and TMEM199 deficiency) is the first that predominantly affects the liver. (34) Mutations in VMA21 cause X-linked myopathy with excessive autophagy (XMEA [MIM: 310440]). XMEA is a disorder associated with progressive muscle weakness.(35,36) Mutations in V-ATPase subunits TCIRG1 (also called ATP6V0A3) and ATP6V0A4 cause tissue-specific symptoms (osteopetrosis [MIM: 259700] and distal renal tubular acidosis [MIM: 602722]).(37,38) A hallmark clinical feature of ATP6V0A2-affected individuals is cutis laxa.(39) Biochemically, ATP6V0A2 deficiency is highly similar to CCDC115 (and TMEM199) deficiency with defective N- and O-glycosylation.(10,40) Interestingly, themost severely affected individual (F5-II1) was diagnosed with redundant skin and poor muscle volume, symptoms characteristic of ATP6V0A2 and VMA21 deficiency, respectively. This hints at a phenotypical continuum among several V-ATPase-associated disorders. The storage-disease-like phenotype of CCDC115 deficiency resembles that of lysosomaldisease,suchasNiemann-PickdiseasetypeC(NPC,causedbymutations in NPC1 and NPC2 [MIM: 257220]). NPC is characterized by hepatosplenomegaly and neurologic manifestations.(41) Lysosomal accumulation of cholesterol and sphingomyelin due to impaired cholesterol trafficking is the hallmark of NPC; hence, NPC can be regarded as a cholesterol trafficking disease.(42) NPC1 and NPC2 work in conjunction with each other and are involved in the transport of cholesterol from late endosomes and lysosomes to the plasma membrane and ER. Interestingly, binding of cholesterol to NPC2 is improved in an acidic environment, and this could be a possible link between CCDC115 deficiency and NPC, given that the V-ATPase is the main acidifier of lysosomal pH.(43) Alternatively, altered trafficking of lysosomal proteins could explain the clinical resemblance. All individuals had elevated serum ALP on biochemical analysis. This was determined to be bone derived for the investigated individuals. Discrepantly