Communicated by Maria Rita Passos-BuenoDiamond-Blackfan anemia (DBA) is an inherited disease characterized by pure erythroid aplasia. Thirty percent (30%) of patients display malformations, especially of the hands, face, heart, and urogenital tract. DBA has an autosomal dominant pattern of inheritance. De novo mutations are common and familial cases display wide clinical heterogeneity. Twenty-five percent (25%) of patients carry a mutation in the ribosomal protein (RP) S19 gene, whereas mutations in RPS24, RPS17, RPL35A, RPL11, and RPL5 are rare. These genes encode for structural proteins of the ribosome. A link between ribosomal functions and erythroid aplasia is apparent in DBA, but its etiology is not clear. Most authors agree that a defect in protein synthesis in a rapidly proliferating tissue, such as the erythroid bone marrow, may explain the defective erythropoiesis. A total of 77 RPS19 mutations have been described. Most are whole gene deletions, translocations, or truncating mutations (nonsense or frameshift), suggesting that haploinsufficiency is the basis of DBA pathology. A total of 22 missense mutations have also been described and several works have provided in vitro functional data for the mutant proteins. This review looks at the data on all these mutations, proposes a functional classification, and describes six new mutations. It is shown that patients with RPS19 mutations display a poorer response to steroids and a worse long-term prognosis compared to other DBA patients. Hum Mutat 29(7), [911][912][913][914][915][916][917][918][919][920] 2008.

Background: In the current SARS-Coronavirus-2 (SARS-CoV-2) pandemic little is known about SARS-CoV-2 in human milk. It is important to discover if breast milk is a vehicle of infection. Objective: Our aim was to look for the presence of SARS-CoV-2 RNA in the milk of a group of SARS-CoV-2 positive mothers from NorthWest Italy. Methods: This is a prospective collaborative observational study where samples of human milk from 14 breastfeeding mothers positive for SARS-CoV-2 were collected. A search of viral RNA in breast milk samples was performed by RT-PCR (Real-Time reverse-transcriptase-Polymerase-Chain-Reaction) methodology tested for human milk. All the newborns underwent a clinical follow up during the first month of life or until the finding of two sequential negative swabs. Results: In 13 cases the search for SARS-CoV-2 RNA in milk samples resulted negative and in one case it was positive. Thirteen of the 14 newborns were exclusively breastfed and closely monitored in the first month of life. Clinical outcome was uneventful. Four newborns tested positive for SARS-CoV-2 and were all detected in the first 48 h of life, after the onset of maternal symptoms. Also the clinical course of these 4 infants, including the one who received mother's milk positive for SARS-CoV-2, was uneventful, and all of them became SARS-CoV-2 negative within 6 weeks of life. Conclusion: Our study supports the view that SARS-CoV-2 positive mothers do not expose their newborns to an additional risk of infection by breastfeeding.

Infantile malignant autosomal recessive osteopetrosis is a genetically heterogeneous disease caused by the inability of OCLs to resorb and remodel bone, resulting in generalized osteosclerosis and obliteration of marrow spaces and cranial foramina. The classical clinical features are pathological fractures, visual impairment, and bone marrow failure.Two human genes have been described as the cause of this form of osteopetrosis: the T-cell immune-regulator-1 (TCIRG1) gene, which is mutated in Ͼ50% of the patients, and the chloride channel 7 (ClCN7) gene, which accounts for ϳ10% of cases. We report the clinical, radiographic, and histopathologic findings of the first human osteopetrosis case caused by a mutation in the grey-lethal (GL) gene. The patient, a 9-day-old male infant, presented with a very severe osteopetrotic phenotype including substantial hepatosplenomegaly since birth, cytopenia, and progressive major liver failure. Skeletal radiographs revealed a generalized increase in bone density with loss of corticomedullary differentiation. Histopathologic bone examination showed the typical osteopetrotic changes, with absence of resorptive activity, and osteoclasts, slightly decreased in number, with evident morphological alterations.

Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in DiamondBlackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locusspecific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care.© 2008 Wiley-Liss, Inc.KEY WORDS: Diamond-Blackfan Anemia, ribosomal protein, erythropoiesis, ribosome biogenesis. INTRODUCTIONDiamond-Blackfan anemia (DBA; MIM# 105650) is a pure red cell aplasia of childhood with an incidence ranging from 5 to 10 cases per million live births in Europe [Campagnoli et al., 2004]. Its main clinical features are normochromic and macrocytic anemia, reticulocytopenia and hypoplasia of erythroid progenitors in the bone marrow, whereas other hematopoietic lineages are usually normal [Campagnoli et al., 2004]. About 30% of patients display somatic abnormalities, involving the upper limbs, head, neck, the urogenital and cardiovascular systems, along with growth retardation. Patients have an increased risk of malignancies [Campagnoli et al., 2004;Lipton et al., 2001]. Management begins with corticosteroids, though the response is variable. Non-responders require multiple blood transfusions. Allogeneic bone marrow or stem cells transplantation is the only curative treatment at present [Roy et al., 2005;Lipton et al., 2006].Ribosomal protein (RP) S19 was the only gene associated with DBA for several years. It is mutated in 25% of patients with either sporadic or familial DBA, always in heterozygosity [Draptchinskaia et al., 1999;Campagnoli et al., 2008]. Mutations in RPS24 have been identified in 3/215 (~2%) DBA probands [Gazda et al., 2006] RPS17 mutation was reported in 1/24 [Cmejla et al., 2007]. Mutations in RPL35A [Farrar et al., 2007], RPL11 and RPL5 have been described, but not yet published in extenso. DBA is thus the only known human disease caused by an RP deficiency and is the prototype of ribosomapathies [Luzzatto and Karadimitris, 1998].The RPS19 gene (MIM# 603474) maps on locus 19q13.2, comprises six exons and spans 11 kb. The first exon (3...

Background:Familial tumoral calcinosis (FTC) is a rare autosomal recessive disease characterised by the development of multiple calcified masses in periarticular soft tissues; GALNT3 gene mutations have recently been described in an African American and in a Druse Arab family with FTC.Objective:To report the clinical and histological features caused by a new GALNT3 mutation in a white family.Results:Homozygosity for the nonsense mutation Lys463X was found in both affected siblings, who displayed a classic phenotype, the male also having testicular microlithiasis. He is the first subject described with testicular microlithiasis in FTC.Conclusions:The high testicular expression of GALNT3 suggests that the gene alteration could act locally by causing deposition of calcium, and the testis may be an underestimated site of calcification in FTC. Autoimmune diseases are present in several members of the family. Although immune disorders have been described in FTC, autoimmunity does not segregate with the GALNT3 mutation in this family.