Single Nucleotide Deletion In Exon Research Articles

FOXJ1 Variants Causing Primary Ciliary Dyskinesia with Hydrocephalus: A Case Report from Japan.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by motile cilia dysfunction, mostly inherited in an autosomal recessive or X-linked manner. We herein report a 29-year-old woman with PCD caused by a heterozygous frameshift mutation due to a single nucleotide deletion in exon 3 of FOXJ1. Heterozygous de novo mutations in FOXJ1 have been reported as an autosomal-dominant cause of PCD. The patient had situs inversus, congenital heart disease, infertility, and hydrocephalus. However, the nasal nitric oxide level was normal. Long-term macrolide therapy was remarkably effective. This is the first case report of PCD caused by a FOXJ1 variant in Japan.

Identification of the novel HLA-C allele, HLA-C*12:351Q, using next-generation sequencing.

The novel allele HLA-C*12:351Q differs from HLA-C*12:02:02:01 by a single nucleotide deletion in exon 5.

Identification of Two Novel Variants of the DMD Gene in Chinese Families with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD), an X-linked recessive neuromuscular disorder, is caused by pathogenic variants in the DMD gene encoding a large structural protein in muscle cells. Two probands, a 6-year old boy and a 1-month old infant, respectively, were clinically diagnosed with DMD based on elevated levels of creatine kinase and creatine kinase isoenzyme. CNVplex and whole exome sequencing (WES) were performed for causal variants, and Sanger sequencing was used for verification. CNVplex found no large deletions or duplications in the DMD gene in both patients, but WES discovered a single-nucleotide deletion in exon 48 (NM_004006.2:c.6963del, p.Asp2322ThrfsTer16) in the proband of pedigree 1, and a nonsense mutation in exon 27 (NM_004006.2:c.3637A>T, p.K1213Ter) in the proband of pedigree 2. The results of our study expand the mutation spectrum of DMD and enrich our understanding of the clinical characteristics of DMD. Genetic counseling was provided for the two families involved in this study.

HLA-C*07:1044N a novel allele, caused by a single nucleotide deletion in exon 3 of HLA-C*07:01:01:01.

HLA-C*07:1044N differs from HLA-C*07:01:01:01 by a single nucleotide deletion in exon 3, codon 124, nt. 442.

Hemoglobinopathy gone astray—three novel forms of α-thalassemia in Norwegian patients characterized by quantitative real-time PCR and DNA sequencing

α-thalassemia is one of the most common monogenic diseases worldwide and is caused by reduced or absent synthesis of α-globin chains, most commonly due to deletions of one or more of the α-globin genes. α-thalassemia occurs with high frequency in tropical and subtropical regions of the world and are very rarely found in the indigenous Scandinavian population. Here, we describe four rare forms of α-thalassemia out of which three are novel, found in together 20 patients of Norwegian origin. The study patients were diagnosed during routine hemoglobinopathy evaluation carried out at the Department of Medical Biochemistry, Oslo University Hospital, Norway. The patients were selected for their thalassemic phenotype, despite Norway as country of origin. All samples went through standard hemoglobinopathy evaluation. DNA sequencing and copy number variation (CNV) analysis using quantitative real-time polymerase chain reaction (qPCR) was applied to detect sequence variants and uncommon deletions in the α-globin gene cluster, respectively. Deletion breakpoints were characterized using gap-PCR and DNA sequencing. DNA sequencing revealed a single nucleotide deletion in exon 3 of the HBA2 gene (NM_000517.4(HBA2):c.345del) and a novel deletion of 20 nucleotides in exon 2 of the HBA2 gene (NM_000517.4(HBA2):c.142_161del). qPCR CNV analysis detected two novel large deletions in the α-globin gene cluster, –(NOR) deletion covering both α-globin genes and (αα)Aurora Borealis affecting the regulatory region, leaving the downstream α-globin genes intact. Even though inherited globin gene disorders are extremely rare in indigenous Scandinavians, the possibility of a carrier state should not be ignored.

Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency

Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes. Genes implicated in mtDNA replication were studied by Next Generation Sequencing (NGS) and whole exome sequence with the TruSeq Rapid Exome kit (Illumina, San Diego, CA, USA). Mitochondrial protein translation was studied following the Sasarman and Shoubridge protocol and oxygen consumption rates with Agilent Seahorse XF24 Analyzer Mitostress Test, (Agilent, Santa Clara, CA, USA). We report two siblings with two novel compound heterozygous pathogenic variants in YARS2 gene: a single nucleotide deletion in exon 1, c.314delG (p.(Gly105Alafs*4)), which creates a premature stop codon in the amino acid 109, and a single nucleotide change in exon 5 c.1391T>C (p.(Ile464Thr)), that cause a missense variant in amino acid 464. We demonstrate the pathogenicity of these new variants associated with reduced YARS2 mRNA transcript, reduced mitochondrial protein translation and dysfunctional organelle function. These pathogenic variants are responsible for late onset MLASA, herein accompanied by pancreatic insufficiency, observed in both brothers, clinically considered as Pearson’s syndrome. Molecular study of YARS2 gene should be considered in patients presenting Pearson’s syndrome characteristics and MLASA related phenotypes.

A Gain-of-Function Mutation in EPO Gene Causes Familial Erythrocytosis

Mutations in the erythropoietin-receptor gene (EPOR) are well known causes of inherited forms of primary erythrocytosis that is characterized by low serum erythropoietin (Epo) levels. Secondary erythrocytosis with elevated Epo serum levels is mainly caused by mutations in genes involved in oxygen sensing pathway. Epo is the primary regulator of erythropoiesis, but mutations in the EPO gene have so far not been described as a cause or erythrocytosis. Here we studied a Norwegian family with autosomal dominant erythrocytosis and elevated Epo serum levels.We performed genome-wide linkage analysis using SNP arrays on 16 informative family members including 10 affected individuals and identified a co-segregating region on chromosome 7q22.1 with a LOD score of 3.3. Targeted sequencing of all 215 genes within the co-segregating region revealed only a heterozygous single base deletion in exon 2 of EPO as the sole candidate gene mutation. ThisΔG deletion creates a frame-shift that truncates the Epo signal peptide and generates a novel peptide, terminating after additional 51 amino acids. Thus, contrary to the expectation based on the erythrocytosis phenotype, the EPO ΔG deletion was predicted to be a loss-of-function mutation.Since we had no access to patient's kidney or liver tissues where Epo is produced, we used the CRISPR technique to introduce the ΔG mutation into the EPO gene into Hep3B cells, a human hepatoma cell line that expresses EPO . We obtained two Hep3B single-cell derived clones (ΔG1 and ΔG4) that were homozygous for the EPO ΔG mutation and measured Epo protein in the culture supernatants. We found that these supernatants contained 8-10 times more Epo than parental Hep3B cells or controls, as determined by ELISA (Figure 1A), and were also capable of stimulating the growth of an Epo-dependent cell line (BaF3- EpoR), demonstrating biological activity (Figure 1B). Thus, the ΔG deletion introduced into the EPO gene locus in Hep3B cells behaved as a gain-of-function mutation.To decipher the mechanism of how the ΔG mutation was able to produce the excess of Epo protein, we searched for alternative EPO mRNAs by 5'-RACE. In addition to the expected transcripts originating from the physiologic promoter (P1) upstream of exon 1, we discovered two types of alternative mRNAs that initiate in intron 1 of EPO. Both initiatied from a putative alternative promoter (P2) in intron 1 that contains two GATA motifs. In addition to Hep3B ΔG clones, P2 transcripts were also detected in parental Hep3B cells and also in mRNA from normal kidney and liver.To determine which transcripts are capable of producing Epo, we transfected HEK293 cells with cDNAs representing P1 or P2 transcripts with or without the ΔG mutation. Supernatants of cells transfected with P2 ΔG transcripts contained more Epo than cells transfected with the wildtype P1 cDNA. These supernatants also stimulated the growth of Epo dependent BaF3- EpoR cells and supported erythroid colony formation of progenitors from human peripheral blood, demonstrating that P2 ΔG transcripts produce biologically active Epo protein.Analysis of the P2 mRNA sequences shows that the normally non-coding P2 transcripts through the ΔG single base deletion connect to the Epo coding sequence creating a functional signal peptide with a novel N-terminus, but retaining the physiologic Epo signal peptide cleavage site. These P2 ΔG transcripts are more abundant in liver and produce an excess of biologically active Epo by escaping the oxygen sensing regulation. Our data demonstrate for the first time mutation in EPO as a cause of familial erythrocytosis and provide an explanation of how the ΔG results in a gain-of-function mutation (Figure 1C).Figure 1 legend: A) Production of Epo protein by He3B cells carrying the ΔG mutation. Supernatants of parental Hep3B or CRISPR-modified Hep3B clones were collected and Epo protein was measured by Epo ELISA. The levels of Epo are given as a mean ± SD (n=3), p < 0.001 = *** as determined by one-way ANOVA. B) Biological activity of Epo produced by parental Hep3B or CRISPR-modified Hep3B cells measured by a proliferation assay with BaF3-EpoR cell line. BaF3-EpoR cells were grown in serial dilutions of supernatants and cell numbers were assessed by Cell Titer-Glo Assay, (n=3). Serial dilutions of 2.5 IU/ml of recombinant human Epo were used for reference. C) Model and proposed mechanism for EPO overproduction by a single nucleotide deletion in exon 2 of the EPO gene. [Display omitted] DisclosuresWaage:Celgene, Takeda: Honoraria. Skoda:Novartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Baxalta: Consultancy, Speakers Bureau.

An IL17RA frameshift variant in a Holstein cattle family with psoriasis-like skin alterations and immunodeficiency

BackgroundSkin lesions and dermatoses in cattle are often associated with infections due to bacteria, fungi or environmental risk factors. Dermatoses with genetic etiology have been described in cattle. Among these rare disorders, there are primary congenital dermatoses that are associated with inherited nutritional deficiencies, such as bovine hereditary zinc deficiency or zinc deficiency-like syndrome. This study presents three cases of Holstein cattle with congenital skin lesions observed on a single farm that resemble zinc deficiency-like syndrome. Close clinical and pathological examinations took place in two cases. Pedigree analysis indicated autosomal recessive inheritance and whole-genome sequencing of both affected calves was performed.ResultsThe two calves showed retarded growth and suffered from severe ulcerative dermatitis with hyperkeratosis, alopecia furunculosis and subcutaneous abscess formation. Blood analysis showed correspondent leukocytosis with neutrophilia whereas minerals, macro- and micronutrients were within the reference ranges. Variant calling and filtering against the 1000 Bull Genomes variant catalogue resulted in the detection of a single homozygous protein-changing variant exclusively present in both sequenced genomes. This single-nucleotide deletion in exon 3 of IL17RA on bovine chromosome 5 was predicted to have a deleterious impact on the encoded protein due to a frameshift leading to a truncated gene product. Genotyping of the affected cattle family confirmed recessive inheritance.ConclusionsA loss-of-function mutation of the IL17RA transmembrane protein could be identified as most likely pathogenic variant for the psoriasis-like skin alterations observed in the two affected Holstein calves. In man, rare recessive diseases associated with IL17RA include immunodeficiency 51 and chronic mucocutaneous candidiasis. This supports the observed immunodeficiency of the presented cases. This study reports the first naturally occurring IL17RA-associated animal model.

Natural single-nucleotide deletion in chymotrypsinogen C gene increases severity of secretagogue-induced pancreatitis in C57BL/6 mice.

Genetic susceptibility to chronic pancreatitis in humans is frequently associated with mutations that increase activation of the digestive protease trypsin. Intrapancreatic trypsin activation is an early event in experimental acute pancreatitis in rodents, suggesting that trypsin is a key driver of pathology. In contrast to trypsin, the pancreatic protease chymotrypsin serves a protective function by mitigating trypsin activation through degradation. In humans, loss-of-function mutations in chymotrypsin C (CTRC) are common risk factors for chronic pancreatitis; however, the pathogenic effect of CTRC deficiency has not been corroborated in animal models yet. Here we report that C57BL/6 mice that are widely used for genetic manipulations do not express functional CTRC due to a single-nucleotide deletion in exon 2 of the Ctrc gene. We restored a functional Ctrc locus in C57BL/6N mice and demonstrated that in the novel Ctrc+ strain the severity of cerulein-induced experimental acute and chronic pancreatitis was significantly ameliorated. Improved disease parameters were associated with reduced intrapancreatic trypsin activation suggesting a causal link between CTRC-mediated trypsinogen degradation and protection against pancreatitis. Taken together with prior human genetic and biochemical studies, the observations provide conclusive evidence for the protective role of CTRC against pancreatitis.

Identification of Two Novel Mutations in KDM3A Regulatory Gene in Iranian Infertile Males

Background:KDM3A is a key epigenetic regulator expressed in the testis and is required for packaging and condensation of sperm chromatin. To this point, the association of the KDM3A gene with infertility has not been studied in human. The aim of this study was to screen any new mutation in KDM3A gene to explore more details of human male infertility.Methods:In this work, 150 infertile men (oligozoospermia and azoospermia) and 150 normal healthy fathers were studied. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing were used to screen any mutation in exons 12, 22, and 24 of KDM3A.Results:The infertile men showed various SSCP patterns for the exons 12 and 24, but not for exon 22. A transversion point mutation in exon 12 and a single nucleotide deletion in exon 24 were detected using sequencing analysis. The transversion mutation was located in the preceding exon of lysine-specific demethylase1 and Jumonji (Jmj)-C domain and the later one (deletion) in the cupin-like motif of KDM3A protein. Neither Y chromosome microdeletions nor partial azoospermia factor deletion was found in these patients.Conclusion:The mutations found in infertile men with otherwise unexplained severe spermatogenic failure could be considered as the origin of their abnormalities.

Hereditary nonspherocytic hemolytic anemia caused by red cell glucose-6-phosphate isomerase (GPI) deficiency in two Portuguese patients: Clinical features and molecular study

Glucose-6-phosphate isomerase (GPI) deficiency cause hereditary nonspherocytic hemolytic anemia (HNSHA) of variable severity in individuals homozygous or compound heterozygous for mutations in GPI gene. This work presents clinical features and genotypic results of two patients of Portuguese origin with GPI deficiency. The patients suffer from a mild hemolytic anemia (Hb levels ranging from 10 to 12.7g/mL) associated with macrocytosis, reticulocytosis, hyperbilirubinemia, hyperferritinemia and slight splenomegaly. Genomic DNA sequencing revealed in one patient homozygosity for a new missense mutation in exon 3, c.260G>C (p.Gly87Ala), and in the second patient compound heterozygosity for the same missense mutation (p.Gly87Ala), along with a frameshift mutation resulting from a single nucleotide deletion in exon 14, c.1238delA (p.Gln413Arg fs*24). Mutation p.Gln413Arg fs*24 is the first frameshift null mutation to be described in GPI deficiency. Molecular modeling suggests that the structural change induced by the p.Gly87Ala pathogenic variant has direct impact in the structural arrangement of the region close to the active site of the enzyme.

Detection of a Novel DSPP Mutation by NGS in a Population Isolate in Madagascar.

A large family from a small village in Madagascar, Antanetilava, is known to present with colored teeth. Through previous collaboration and 4 successive visits in 1994, 2004, 2005, and 2012, we provided dental care to the inhabitants and diagnosed dentinogenesis imperfecta. Recently, using whole exome sequencing we confirmed the clinical diagnosis by identifying a novel single nucleotide deletion in exon 5 of DSPP. This paper underlines the necessity of long run research, the importance of international and interpersonal collaborations as well as the major contribution of next generation sequencing tools in the genetic diagnosis of rare oro-dental anomalies. This study is registered in ClinicalTrials (https://clinicaltrials.gov) under the number NCT02397824.

P95 – 3007: Late onset treatment on Menkes disease with a novel single nucleotide deletion in the ATP7A gene

Objective Menkes disease (MD) is an X-linked recessive disorder of copper metabolism caused by mutations in the ATP7A gene. A genotype-phenotype correlation is crucial since early copper treatment contributes to a better neurodevelopmental outcome and longer survival. We report a case with a novel mutation of a single nucleotide deletion which revealed unexpectedly less severe clinical manifestations, while copper treatment was initiated at 23 months old. Methods The index patient at 12 months old had severe hypotonia, ataxia, connective tissue abnormalities, while his mental abilities were satisfactory and no seizures had occurred. Brain MRA revealed pronounced vessel tortuosity. The serum concentration of copper and ceruloplasmin was slightly reduced. The ATP7A gene screening identified a de novo mutation c.368delG in exon 3 and copper uptake was clearly indicative of MD. Subcutaneous copper histidine treatment was initiated at the age of 23 months assuming that less severe phenotype implies residual ATP7A activity. Western Blot analysis was investigated for ATP7A function. Results After 4½ years of copper treatment the child shows a slow but steady improvement in his development. His muscle tone is improving and he is able to stand on his own, however, truncal ataxia is still present. Although not able to speak, he is very communicative. Until now he has no epilepsy. Pili torti disappeared, but there is no change on his joint and skin laxity and vessel tortuosity. Western Blot analysis shows no presence of ATP7A protein. Conclusion A single nucleotide deletion in exon 3 is expected to abolish ATP7A function and result to a severe clinical phenotype. The moderate severity of patient's clinical manifestations, the unfavorable nature of his mutation along with the lack of detection of ATP7A protein in Western Blot analysis speculates that the late-onset treatment with copper histidine may have a favorable effect.

Molecular diagnosis of distal renal tubular acidosis in Tunisian patients: proposed algorithm for Northern Africa populations for the ATP6V1B1, ATP6V0A4 and SCL4A1genes

BackgroundPrimary distal renal tubular acidosis (dRTA) caused by mutations in the genes that codify for the H + −ATPase pump subunits is a heterogeneous disease with a poor phenotype-genotype correlation. Up to now, large cohorts of dRTA Tunisian patients have not been analyzed, and molecular defects may differ from those described in other ethnicities. We aim to identify molecular defects present in the ATP6V1B1, ATP6V0A4 and SLC4A1 genes in a Tunisian cohort, according to the following algorithm: first, ATP6V1B1 gene analysis in dRTA patients with sensorineural hearing loss (SNHL) or unknown hearing status. Afterwards, ATP6V0A4 gene study in dRTA patients with normal hearing, and in those without any structural mutation in the ATP6V1B1 gene despite presenting SNHL. Finally, analysis of the SLC4A1 gene in those patients with a negative result for the previous studies.Methods25 children (19 boys) with dRTA from 20 families of Tunisian origin were studied. DNAs were extracted by the standard phenol/chloroform method. Molecular analysis was performed by PCR amplification and direct sequencing.ResultsIn the index cases, ATP6V1B1 gene screening resulted in a mutation detection rate of 81.25%, which increased up to 95% after ATP6V0A4 gene analysis. Three ATP6V1B1 mutations were observed: one frameshift mutation (c.1155dupC; p.Ile386fs), in exon 12; a G to C single nucleotide substitution, on the acceptor splicing site (c.175-1G > C; p.?) in intron 2, and one novel missense mutation (c.1102G > A; p.Glu368Lys), in exon 11. We also report four mutations in the ATP6V0A4 gene: one single nucleotide deletion in exon 13 (c.1221delG; p.Met408Cysfs*10); the nonsense c.16C > T; p.Arg6*, in exon 3; and the missense changes c.1739 T > C; p.Met580Thr, in exon 17 and c.2035G > T; p.Asp679Tyr, in exon 19.ConclusionMolecular diagnosis of ATP6V1B1 and ATP6V0A4 genes was performed in a large Tunisian cohort with dRTA. We identified three different ATP6V1B1 and four different ATP6V0A4 mutations in 25 Tunisian children. One of them, c.1102G > A; p.Glu368Lys in the ATP6V1B1 gene, had not previously been described. Among deaf since childhood patients, 75% had the ATP6V1B1 gene c.1155dupC mutation in homozygosis. Based on the results, we propose a new diagnostic strategy to facilitate the genetic testing in North Africans with dRTA and SNHL.

Bimodal evolution of the killer cell Ig-like receptor (KIR) family in New World primates

The immunoglobulin-like receptor (KIR) gene family in New World primates (Platyrrhini) has been characterized only in the owl monkey (Aotus sp.). To gain a better understanding of the KIR system in Platyrrhini, we analyzed a KIR haplotype in Ateles geoffroyi, and sequenced KIR complementary DNAs (cDNAs) from other three Atelidae species, Ateles hybridus, Ateles belzebuth, and Lagothrix lagotricha. Atelidae expressed a variable set of activating and inhibitory KIRs that diversified independently from their Catarrhini counterparts. They had a unique mechanism to generate activating receptors from inhibitory ones, involving a single nucleotide deletion in exon 7 and a change in the donor splice site of intron 7. The A. geoffroyi haplotype contained at least six gene models including a pseudogene, two coding inhibitory receptors, and three coding activating receptors. The centromeric region was in a tail-to-tail orientation with respect to the telomeric region. The owl monkey KIR haplotype shared this organization, and in phylogenetic trees, the centromeric genes clustered together with those of A. geoffroyi, whereas their telomeric genes clustered independently. KIR cDNAs from the other Atelidae species conformed to this pattern. Signatures of positive selection were found in residues predicted to interact with the major histocompatibility complex. Such signatures, however, primarily explained variability between paralogous genes but not between alleles in a locus. Atelidae, therefore, has expanded the KIR family in a bimodal fashion, where an inverted centromeric region has remained relatively conserved and the telomeric region has diversified by a rapid process of gene duplication and divergence, likely favored by positive selection for ligand binding.

Identification of a new HLA‐A*02 allele, HLA‐A*02:305 N, which differs from the HLA‐A*02:01:01 allele by a single nucleotide deletion in exon 4

The HLA-A*02:305N new allele lacks a nucleotide in exon 4 compared to HLA-A*02:01:01 allele.

A single nucleotide deletion in exon 2 produces a novel null allele, HLA-DRB1*01:33N

A single nucleotide deletion in codon 12 of the human leukocyte antigen HLA-DRB1*01 results in a novel null allele, DRB1*01:33N.

High Frequency of RPL11 Gene Mutation in Italian Patients with Diamond-Blackfan Anemia

Diamond Blackfan anemia (DBA, MIM#205900) is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of cases show malformations. Anemia is corrected by steroid treatment in half of the patients; non-responders need chronic transfusions or stem cell transplantation.Defects in the RPS19 gene, encoding the ribosomal protein (RP) S19, are the main known cause of DBA and account for more than 25% of patients. Mutations in other RPs (RPS24, RPS17, RPL35a) have been reported in a minority of patients (Gazda et al., 2006; Cmejla et al., 2007; Farrar et al., 2008) and show that DBA is a disorder of ribosome synthesis. Recently, Gadza et al. (2007) reported the involvement of two new genes (RPL5, RPL11) encoding for RPs of the large subunit in a considerable percentage of DBA patients without mutations in RPS19 or RPS24 (10% and 6,5%, respectively).Here we present the results of RPL11 mutation screening in Italian DBA patients without RPS19 or RPS24 mutations. Preliminary data of RPL5 analysis are also reported.The human RPL11 gene includes 6 exons and spans 4622 bp on chromosome 1. We identified 12 heterozygous mutations in 80 analyzed probands (15%), 10 of which were deletions of 1–47 nucleotides causing frameshift and a premature termination; another deletion (12nt) resulted in a loss of 4 aminoacids. One acceptor splice site defect (intron 5) was also detected. RPL11 mutations were spread in all exons except for exon 1.The human RPL5 gene spans 9888 bp on chromosome 1, and includes 8 exons. We identified one heterozygous mutation in RPL5 in 14 analyzed patients (7%); it is a single nucleotide deletion in exon 5 causing frameshift and a premature termination.None of these sequence changes were found on the NCBI SNP dalabase (http://www.ncbi.nlm.nih.gov/SNP/).Our mutations are expected to alter the genetic information drastically and to cause haploinsufficency. Depletion of RPs compromises ribosome biogenesis and disturbs rRNA processing at different levels (Robledo et al. 2008).Interestingly, all mutated patients (11/13) showed one or more somatic malformations; specifically, thumb anomalies and growth retardation were present in 7/11 (64%) and 6/11 (54%) patients, respectively. The erythrocyte adenosine deaminase activity was performed in 6/13 mutated patients; all of them showed an increased activity. The majority of RPL11 mutated patients were transfusion-dependent at last follow-up (58%,7/12); the RPL5 mutated patient was in clinical remission after steroid treatment. No one of the mutated patients has so far developed neoplasia.Our data show that RPL11 mutations are more frequent than expected (Gazda et al. 2007). They seem to confer a relevant association with a malformation phenotype as compared to RPS19 mutations.

Familial hypobetalipoproteinemia in a Turkish family with hereditary spastic paraplegia

A 24-year-old male presented with progressive gait disturbance and was diagnosed with hereditary spastic paraplegia. His brother and possibly one uncle also had the condition. Routine biochemical testing found that the patient had unusually low plasma concentrations of low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B, the hallmark of familial hypobetalipoproteinemia. DNA sequencing showed that he, along with other family members ( n = 5; mean LDL cholesterol 0.8 mmol/L, apoB 0.31 g/L), were heterozygous for a single nucleotide deletion in exon 26 of the APOB gene. This mutation is predicted to form a truncated apoB species of 3545 amino acids, which we have designated apoB-78.2.

A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies

We describe a Japanese family with familial platelet disorder with propensity to develop myeloid malignancies (FPD/MM). Among the three affected individuals, two members developed myeloid malignancies. Sequence studies demonstrate that all affected individuals of the pedigree display a heterozygous single nucleotide deletion in exon 8 of the RUNX1 gene.