KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann–Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin–Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein–Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and in recent decades, epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. To note, pharmaceutical compounds acting on tumors characterized by KMT2A mutations have been formulated, and even nutritional interventions for chromatinopathies have become the object of study due to the role of microbiota in epigenetic regulation.

Background: Poikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused byC16orf57mutations. To date 17 mutations have been identified in 31 PN patients.Results: We characterize six PN patients expanding the clinical phenotype of the syndrome and the mutational repertoire of the gene. We detect the two novelC16orf57mutations, c.232C>T and c.265+2T>G, as well as the already reported c.179delC, c.531delA and c.693+1G>T mutations. cDNA analysis evidences the presence of aberrant transcripts, and bioinformatic prediction of C16orf57 protein structure gauges the mutations effects on the folded protein chain.Computational analysis of the C16orf57 protein shows two conserved H-X-S/T-X tetrapeptide motifs marking the active site of a two-fold pseudosymmetric structure recalling the 2H phosphoesterase superfamily. Based on this model C16orf57 is likely a 2H-active site enzyme functioning in RNA processing, as a presumptive RNA ligase.According to bioinformatic prediction, all knownC16orf57mutations, including the novel mutations herein described, impair the protein structure by either removing one or both tetrapeptide motifs or by destroying the symmetry of the native folding.Finally, we analyse the geographical distribution of the recurrent mutations that depicts clusters featuring a founder effect.Conclusions: In cohorts of patients clinically affected by genodermatoses with overlapping symptoms, the molecular screening ofC16orf57gene seems the proper way to address the correct diagnosis of PN, enabling the syndrome-specific oncosurveillance.The bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function. Detection of aberrant transcripts, also in cells from PN patients carrying early truncated mutations, suggests they might be translatable. Tissue-specific sensitivity to the lack of functionally correct protein accounts for the main cutaneous and haematological clinical signs of PN patients.

Integrin α3 (ITGA3) gene mutations are associated with Interstitial Lung disease, Nephrotic syndrome and Epidermolysis bullosa (ILNEB syndrome). To date only six patients are reported: all carried homozygous ITGA3 mutations and presented a dramatically severe phenotype leading to death before age 2 years, from multi-organ failure due to interstitial lung disease and congenital nephrotic syndrome. The involvement of skin and cutaneous adnexa was variable with sparse hair and nail dysplasia combined or not to skin lesions ranging from skin fragility to epidermolysis bullosa-like blistering. We report on two siblings of 13 and 9 years born to non-consanguineous healthy parents, who display growth delay, severe pulmonary fibrosis with fatigue, dyspnea on exertion and wheezing, atrophic skin with erythematosus lesions, rare eyelashes/eyebrows and pachyonychia. By exome sequencing, we identified two unreported ITGA3 missense mutations, c.373G>A (p.(G125R)) in exon 3 and c.821G>A (p.(R274Q)) in exon 6, affecting highly conserved residues in the integrin α3 extracellular N-terminal β-propeller domain. Homology modelling of α3β1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the β-propeller, while R274 might prevent the interaction between integrin and urokinase complex. We report a variant of ILNEB syndrome in two siblings differing from the previously reported patients in the lack of nephrotic impairment and survival beyond childhood. Our siblings are the first reported compound heterozygous for ITGA3 mutations; this state as well as the hypomorphic nature of their p.(R274Q) mutation likely account for their survival.