Loss-of-function variants in ATP6V0A2, encoding the trans Golgi V-ATPase subunit V0a2, cause wrinkly skin syndrome (WSS), a connective tissue disorder with glycosylation defects and aberrant cortical neuron migration. We used knock-out (Atp6v0a2-/-) and knock-in (Atp6v0a2RQ/RQ) mice harboring the R755Q missense mutation selectively abolishing V0a2-mediated proton transport to investigate the WSS pathomechanism. Homozygous mutants from both strains displayed a reduction of growth, dermis thickness, and elastic fiber formation compatible with WSS. A hitherto unrecognized male infertility due to globozoospermia was evident in both mouse lines with impaired Golgi-derived acrosome formation and abolished mucin-type O-glycosylation in spermatids. Atp6v0a2-/- mutants showed enhanced fucosylation and glycosaminoglycan modification, but reduced levels of glycanated decorin and sialylation in skin and/or fibroblasts, which were absent or milder in Atp6v0a2RQ/RQ. Atp6v0a2RQ/RQ mutants displayed more abnormal migration of cortical neurons, correlating with seizures and a reduced O-mannosylation of α-dystroglycan. While anterograde transport within the secretory pathway was similarly delayed in both mutants the brefeldin A-induced retrograde fusion of Golgi membranes with the endoplasmic reticulum was less impaired in Atp6v0a2RQ/RQ. Measurement of the pH in the trans Golgi compartment revealed a shift from 5.80 in wildtype to 6.52 in Atp6v0a2-/- and 6.25 in Atp6v0a2RQ/RQ. Our findings suggest that altered O-glycosylation is more relevant for the WSS pathomechanism than N-glycosylation and leads to a secondary dystroglycanopathy. Most phenotypic and cellular properties correlate with the different degrees of trans Golgi pH elevation in both mutants underlining the fundamental relevance of pH regulation in the secretory pathway. ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression. The diagnosis of ATP6V0A2-related cutis laxa is established by the presence of suggestive findings and biallelic pathogenic variants in ATP6V0A2 identified by molecular genetic testing. Treatment of manifestations: Standard treatment for congenital hip dislocation, inguinal hernias, high myopia, and seizure disorders. Early intervention and management of developmental delays and intellectual disability and psychological help as needed for self-image issues. Surveillance: Annual ophthalmologic examination, EEG, and monitoring of anticonvulsive drug levels. ATP6V0A2-related cutis laxa is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ATP6V0A2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ATP6V0A2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for ATP6V0A2-related cutis laxa are possible.

Previously, we reported that the hot water extract of Hydrangea serrata leaves (WHS) and its active component, hydrangenol, possess in vitro and in vivo effects on skin wrinkles and moisturization. We conducted a randomized, double-blind, placebo-controlled trial to clinically evaluate the effect of WHS on human skin. Participants (n = 151) were randomly assigned to receive either WHS 300 mg, WHS 600 mg, or placebo, once daily for 12 weeks. Skin wrinkle, hydration, elasticity, texture, and roughness parameters were assessed at baseline and after 4, 8, and 12 weeks. Compared to the placebo, skin wrinkles were significantly reduced in both WHS groups after 8 and 12 weeks. In both WHS groups, five parameters (R1-R5) of skin wrinkles significantly improved and skin hydration was significantly enhanced when compared to the placebo group after 12 weeks. Compared with the placebo, three parameters of skin elasticity, including overall elasticity (R2), net elasticity (R5), and ratio of elastic recovery to total deformation (R7), improved after 12 weeks of oral WHS (600 mg) administration. Changes in skin texture and roughness were significantly reduced in both WHS groups. No WHS-related adverse reactions were reported. Hence, WHS could be used as a health supplement for skin anti-aging.

Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.

Cutis laxa is a heterogeneous group of diseases, with loose, wrinkled skin folds and hyperelasticity of the skin. There are overlapping of clinical features of the group of syndrome associated with cutis laxa, including congenital cutis laxa, wrinkly skin syndrome and gerodermia osteodysplastica. All these conditions present a challenge to the clinician. Thus, molecular diagnosis is the only way to resolve these phenotypically similar conditions. We hereby describe two Indian patients with wrinkled skin and mild craniofacial dysmorphic features who had molecular confirmation of autosomal recessive cutis laxa.