Mutations In Different Genes Research Articles

Circulating free DNA as a surrogate for tumor material for EGFR and KRAS analysis

Abstract The analysis of a patient's tumor mutation status has become increasingly important. Pharmaceuticals such as gefitinib require that a mutation test is performed prior to treatment to help predict a positive outcome to the patient before the drug is administered. However, obtaining a suitable tumor sample for analysis is not always possible and therefore some patients that may benefit will not receive the drug. The use of easily obtainable samples such as plasma or serum would be ideal if tumor derived material could be readily extracted and contained the same predictive mutations as the source tumor. We have evaluated circulating free (cf) DNA from plasma, and to a lesser extent serum, from lung cancer patients for EGFR and KRAS mutations using allele specific PCR tests (ARMSTM). The majority of the samples had no matched tumor sample available so the mutation detection rate was compared to the expected frequency of mutations in this tumor and population type. EGFR mutations were detected in 21 of 237 plasma cf DNA samples (8.9%) (expected: 10-15%). KRAS mutations were detected in 11 of 168 plasma cf DNA samples (6.6%) (expected: 17%). Where analysis was performed on the matched cf DNA extracted from serum the mutation detection rate was lower than in plasma. Interestingly the EGFR mutation frequency was higher than KRAS in the plasma samples, although the KRAS mutation frequency was expected to be higher than EGFR mutation frequency in the tumors. This could be due to the frequent amplification of mutant EGFR in lung tumors resulting in more target copies in the cf DNA, the EGFR assays could be more sensitive or perhaps the nature of EGFR mutation containing tumors is different making them shed more DNA or survive longer in the blood. In conclusion, cf DNA derived from plasma is a useful surrogate for mutation detection when no tumor sample is available, but the mutation detection rate is not equal for different mutations in different genes.

P2.18 A novel missense FLNC mutation causes arrhythmia and late onset myofibrillar myopathy with particular histopathology features

Myofibrillar myopathy (MFM) is an adult onset disease characterized by myofibrillar destruction and the presence of protein aggregates in the sarcoplasm. It is caused by mutations in different genes that express proteins of the Z disc of the sarcomere, including FLNC.

The new IC3D nomenclature of corneal dystrophies

Abstract Purpose Advances in genotyping have challenged the significance of the entities called the corneal dystrophies. Although the term corneal dystrophy typically refers to a group of inherited corneal disease that are bilateral, symmetric, slowly progressive and without relation to sytemic disease or environmental factors; exceptions to each part of the definition exist. Mutations in different genes can result in one phenotype and mutations in one gene can result in different allelic dystrophy phenotypes. The phenotypic classification system has become archaic. The International Committee on the Classification of Corneal Dystrophies (ICD3) was created in 2005 to revise the corneal dystrophy nomenclature. Methods A critical evaluation of the literature to remove inaccurate information and distil the facts was performed by an international panel of world experts including geneticists, pathologist and ophthalmologists. A template was created for each dystrophy which summarized the genetic, clinical and pathologic information with accompanying clinical photographs. Each dystrophy was reviewed to determine if there was an identified gene, gene locus and whether it was clinically well defined. Results The dystrophies were organized anatomically and each dystrophy was assigned a category from 1 to 4 indicating the level of evidence supporting the existence of a given dystrophy. Category 1‐ A well defined dystrophy with known gene locus and gene Category 2‐ A well defined dystrophy with known gene locus, unknown gene Category 3‐ A well defined dystrophy with unknown gene locus and gene Category 4‐ A poorly defined dystrophy with unknown gene locus and gene Conclusion The IC3D nomenclature system is available online at www.corneasociety.org in English and Spanish. A German translation has just been completed.

Génétique et métabolisme osseux

The importance of genetic factors in osteoporosis is well known. Their identification would allow us to better understand the physiopathology of this affection, and may be, to predict the fracture risk better and lead to the development of new treatments. A large number of studies concerning candidate genes implied in different bone metabolism pathways and more recent genome-wide association studies have been carried out but the contribution of the genes identified at present remains modest. Some advances have been made in understanding the pathogenesis of hypophosphatemic rickets with the discovery of the mutations of different genes ( PHEX, FGF23, DMP1, SLC34A3), and of hypophosphatasia, which is accompagnied by the mutation of the gene encoding tissue-nonspecific alkaline phosphatase.

An integrated approach to the diagnosis of muscle disorders: what is the role of muscle imaging?

Since the discovery of mutations in the dystrophin gene in 1987, there has been a string of exciting genetic discoveries in the field of inherited neuromuscular disorders, with an always increasing number of genetically recognized forms of muscle disorder.1 This has allowed the identification of new clinical entities and a better understanding of the mechanisms underlying the individual disorders. It has also become obvious that for some neuromuscular disorders we can no longer accept such simplistic equations as ‘one gene equals one disease’ and conversely, ‘one disease equals one gene’. It is now well recognized that a gene can be associated with different disorders (e.g. lamin A/C; phenotypic divergence) and that one disease can be caused by several genes (phenotypic convergence). The best example of phenotypic divergence in muscle disorders comes from the forms of congenital muscular dystrophy with muscle, eye, and brain involvement (Muscle-Eye-Brain disease and Walker-Waburg syndrome) that have been found to be associated with mutations in different genes.2 The complexity of all these new clinically and genetically distinct entities has made the diagnostic process more difficult, especially for the muscle disorders sharing clinical and biopsy findings with other genetically distinct entities. This issue is particularly relevant in young children. In older patients there are often clinical signs, such as the presence and the type of cardiac or respiratory impairment or the pattern of weakness and contractures that may provide important clues for targeting the appropriate genetic investigations. In young children however, clinical signs at onset can be mild and non-specific and the differential diagnosis can be difficult. Muscle biopsy is often highly important in identifying structural or immunohystochemical changes that may help to arrive at a specific diagnosis. In a number of cases, however, these markers, even when present, will help to identify the family of disorders but not always the gene involved. A few examples may illustrate the point. Structural changes such as cores or nemaline rods can be found in several forms of nemaline or core myopathies, but this will not predict the gene involved.3 Similarly, the detection of alpha dystroglycan deficiency on muscle biopsy will help to identify the group of disorders but not which gene is responsible for an individual case.2 There is increasing evidence that muscle imaging may help as an additional tool in the differential diagnosis of muscle disorders with clinical overlap. Since the early studies on muscle imaging in the 1970s using muscle ultrasound or computed tomography (CT),4 it has been reported that in patients with inherited neuromuscular disorders not all muscles are equally affected and individual muscles can be selectively affected or spared. Following the identification of the genetic defect in several muscle disorders, a number of papers have suggested that genetically distinct entities have different patterns of muscle involvement and that these patterns appear to be consistent within individual forms of muscle disorders. These changes can be seen on ultrasound or CT but are better appreciated on muscle magnetic resonance imaging (MRI) that has several advantages over CT, such as the absence of ionizing radiations and the possibility to use multiplanar imaging. Although we are still in a learning phase, there are more and more studies reporting the value of muscle MRI in an increasing number of disorders and its sensitivity and specificity in identifying disease-specific patterns in large series of patients with significant clinical overlap. In a recent study assessing scans from 83 patients with muscle disorders characterized by rigidity of the spine secondary to mutations in four different genes, we found that the sensitivity to detect selective patterns in relation to the genetic diagnosis was 0.9.5 These findings do not mean that muscle MRI will replace clinical examination or muscle biopsy but that we need to address the differential diagnosis in this field with an integrated approach, taking advantage of the information provided by each of these tools. Going back to the example of congenital myopathies, muscle biopsy will help to identify the group of disorders, e.g. central core or nemaline myopathies. A detailed family history, the evaluation of the modality of inheritance, clinical signs and, finally, muscle MRI will help to target the most appropriate genetic investigation. Much can be gained by this approach, saving time, money, and anxiety, making a difference for the children and their families both for genetic counselling and for management.

The Genetics of Malignant Hyperthermia and Related Muscular Syndromes

To the Editor: The review by Capacchione and Muldoon1 discusses relationships between malignant hyperthermia (MH) and other muscular diseases presenting with some of the clinical features of MH. The task is made more difficult because of the uncertain relationships between a positive in vitro contracture test for halothane and caffeine, specific expression of the triggering mechanism of MH, and the presence of a genetic defect in the muscular ryanodine receptor type 1 (RYR1) gene. Capacchione and Muldoon state that “a negative RYR1 screen with a positive contracture test does not necessarily mean that the patient is not MH susceptible as there are likely yet unidentified non-RYR1 mutations that confer MHS (MH susceptibility).” Indeed, in the 20% to 30% of individuals lacking an RYR1 mutation, genetic alterations of other proteins involved in calcium release or its regulation could be present.2 Monnier et al.3 described such a mutation in the α-1 subunit of the human dihydropyridine receptor responsible for MH in a French family. Protasi et al.2 and Dainese et al.,4 studying knockout mice lacking skeletal muscle calsequestrin, a calcium-binding and buffering protein involved in the modulation of calcium release from RYR1, suggested that this mutation could be involved in MH and environmental heat stroke. On the basis of analogies between MH and catecholaminergic polymorphic ventricular tachycardia, a cardiac disorder caused by mutation in the cardiac RYR2 gene, MacLennan and Chen5 suggested that both diseases may have a common mechanism. In fact, a mutation in RyR can decrease the threshold for calcium release from sarcoplasmic reticulum, and a mutation in calsequestrin can increase the free calcium concentration over the same threshold, giving rise, in the presence of halothane and catecholamines, to contracture (MH) or arrhythmias (catecholaminergic polymorphic ventricular tachycardia), respectively. It is also possible that a mutation in different genes involved in the production and regulation of different calcium handling proteins could explain not only MH and similar muscular diseases but also some cardiac-related diseases sharing the same genetic anomaly. Luca Siracusano, MD Viviana Girasole, MD Department of Neuroscience, Psychiatric and Anesthesiological Sciences University of Messina Messina, Italy [email protected] or [email protected]

The genetic and evolutionary basis of colour variation in vertebrates.

Variation in pigmentation is one of the most conspicuous phenotypic traits in vertebrates. Although mammals show less variation in body pigmentation than other vertebrate groups, the genetics of colour determination and variation is best understood for them. More than 150 genes have been identified that influence pigmentation, and in many cases, the cause for variation in pigmentation has been identified down to the underlying nucleotide changes. These studies show that while some genes are often responsible for deviating pigmentation, similar or almost identical phenotypes even in the same species may be due to mutations in different genes. In this review we will first discuss the current knowledge about the genes and their functions underlying the biochemical pathways that determine pigmentation and then give examples where the mutations responsible for colour variation have been determined. Finally, we will discuss potential evolutionary causes for and consequences of differences in pigmentation between individuals.

Digenic mutations in severe congenital neutropenia

Severe congenital neutropenia a clinically and genetically heterogeneous disorder. Mutations in different genes have been described as causative for severe neutropenia, e.g. ELANE, HAX1 and G6PC3. Although congenital neutropenia is considered to be a group of monogenic disorders, the phenotypic heterogeneity even within the yet defined genetic subtypes points to additional genetic and/or epigenetic influences on the disease phenotype. We describe congenital neutropenia patients with mutations in two candidate genes each, including 6 novel mutations. Two of them had a heterozygous ELANE mutation combined with a homozygous mutation in G6PC3 or HAX1, respectively. The other 2 patients combined homozygous or compound heterozygous mutations in G6PC3 or HAX1 with a heterozygous mutation in the respective other gene. Our results suggest that digenicity may underlie this disorder of myelopoiesis at least in some congenital neutropenia patients.

Genetic basis of oculocutaneous albinism

Oculocutaneous albinism (OCA) is generally considered as an autosomal recessive disorder characterized by skin, hair and eye hypopigmentation. Its worldwide prevalence is approximately one out of 20,000. The four OCA types (OCA1–4) are not represented equally in different populations. OCA1–4 are caused by mutations in different genes: TYR in 11q14.3 (OCA1), OCA2 in 15q12 (OCA2), TYRP1 in 9p23 (OCA3) and SLC45A2 in 5p13.3 (OCA4). Molecular analysis of the four genes indicates that some mutations escape detection, and suggests that other OCA genes may exist. The pigmentation phenotype of the patients is largely modified by polymorphisms at a variety of loci throughout the genome, including the OCA loci themselves. OCA stands out as a paradigm of genetic disease influenced by the genetic background.

Genetic syndromes involving hearing

Objective The fundamental processes involved in the mechanism of hearing seem to be controlled by hundreds of genes and hereditary hearing impairment may be caused by a large variety of genetic mutations in different genes. Approximately 150 loci for monogenic syndromic and non-syndromic hearing impairment (HI) disorders have been mapped to the human genome. The identification of these genes and functional analysis of the proteins they encode, are paving the way towards a better understanding of the physiology and pathophysiology of the auditory system. To date, approximately 50 causative genes have been identified. Methods The clinical and neuroradioldical findings of syndromal hearing impairment are analysed. Results This paper presents an updated report on genetic syndromes in which a hearing impairment is involved, with a particular attention to the ones associated with external ear and craniofacial malformations. Conclusions Concepts in human genetics are rapidly evolving together with technologies. The concept itself of gene is changing. A genetic diagnosis of syndromal hearing impairment has many practical consequences: it can implies specific prognosis, specific management, specific recurrence risk in relatives and, if the diagnosis is confirmed at the molecular level, possibility of a specific early prenatal diagnosis for severe syndromes. It is important to highlight the necessity that the pediatric otolaryngologist must have a close collaboration with a clinical geneticist and a neuroradiologist.

Nature’s Genetic Gradients and the Clinical Phenotype

When God created the earth, he placed (modern) mankind in East Africa ≈200 000 years ago, as suggested by the phylogenetic and archeological studies.1,2 These hunter-gatherers populated the land and started to migrate, first to the west and southern tip of Africa and then north toward North Africa. Mankind gradually crossed the Arabian Peninsula to the Middle East and Eurasia. Then, over thousands of years of northerly movement, man crossed the Bering land bridge that connected Siberia to Alaska and migrated down to the Americas. This out-of-Africa migration took thousands of generations. It was interrupted by the Ice Age, which led to depopulation and isolation of the surviving population followed by the new waves of migrations, resulting in multiple founding populations.3 Articles see pages 552 and 558 At the genetic level, the tree of life was produced through replication of the genome. For the genome to replicate, cells are equipped with DNA polymerases to copy the parental DNA, which they do at blazing speeds.4 However, “no protein is perfect,” and neither are the DNA polymerases. So, the DNA polymerases commit occasional errors in copying the template (parental) DNA and incorporate wrong nucleotides into the new DNA strands. To correct the errors, nature afforded the cells with DNA repair enzymes, which are assigned the task of maintaining the integrity of the nucleotide pools before replication.5 Nevertheless, the process of DNA replication and editing, although exceedingly precise, is imperfect. The error rate of the DNA replication and editing machinery is estimated to be at 10−6 to 10−10 nucleotides incorporated into the new strand of DNA.6,7 The inheritance is forward. Therefore, the misincorporated nucleotides are passed on to the next generation, and with each generation, new errors in DNA replication are introduced. The occasional “errors of …

The genetics of status epilepticus

Many common diseases and disorders, such as hypertension, diabetes, arthritis, and epilepsy, have a genetic component with a complex genetic architecture. Evidence for a genetic influence on epilepsy emerged in twin studies that reported concordance rates consistently higher in monozygotic than in dizygotic twins (Lennox, 1951; Sillanpaa et al., 1991; Berkovic et al., 1998). The causation of epilepsy is multifactorial (a combination of environmental and genetic risk factors), and the genetic part is very complex (polygenic). For example, mutations in different genes can cause the same syndromes in different families (Cossette et al., 2002; Suzuki et al., 2004). Equally concerning is the second complication of variable expressivity, in which mutations in a single gene can produce different epilepsy phenotypes in different individuals as a result of modifying genetic or environmental factors (Kanai et al., 2004; Mulley et al., 2005). Therefore, similar to many other complex diseases, it has been suggested that epilepsy is a polygenic syndrome, influenced by the effect of variation at several or multiple genes (reviewed in Ottman et al., 1996; Anderson et al., 2002).

Multilevel complex interactions between genetic, epigenetic and environmental factors in the aetiology of anomalies of dental development

Dental anomalies are caused by complex interactions between genetic, epigenetic and environmental factors during the long process of dental development. This process is multifactorial, multilevel, multidimensional and progressive over time. In this paper the evidence from animal models and from human studies is integrated to outline the current position and to construct and evaluate models, as a basis for future work.Dental development is multilevel entailing molecular and cellular interactions which have macroscopic outcomes. It is multidimensional, requiring developments in the three spatial dimensions and the fourth dimension of time. It is progressive, occurring over a long period, yet with critical stages. The series of interactions involving multiple genetic signalling pathways are also influenced by extracellular factors. Interactions, gradients and spatial field effects of multiple genes, epigenetic and environmental factors all influence the development of individual teeth, groups of teeth and the dentition as a whole. The macroscopic, clinically visible result in humans is a complex unit of four different tooth types formed in morphogenetic fields, in which teeth within each field form directionally and erupt at different times, reflecting the spatio-temporal control of development.Even when a specific mutation of a single gene or one major environmental insult has been identified in a patient with a dental anomaly, detailed investigation of the phenotype often reveals variation between affected individuals in the same family, between dentitions in the same individual and even between different teeth in the same dentition. The same, or closely similar phenotypes, whether anomalies of tooth number or structure, may arise from different aetiologies: not only mutations in different genes but also environmental factors may result in similar phenotypes. Related to the action of a number of the developmental regulatory genes active in odontogenesis, in different tissues, mutations can result in syndromes of which dental anomalies are part. Disruption of the antagonistic balance between developmental regulatory genes, acting as activators or inhibitors can result in dental anomalies. There are critical stages in the development of the individual tooth germs and, if progression fails, the germ will not develop further or undergoes apoptosis. The reiterative signalling patterns over time during the sequential process of initiation and morphogenesis are reflected in the clinical association of anomalies of number, size and form and the proposed models.An initial step in future studies is to combine the genetic investigations with accurate recording and measurement of the phenotype. They also need to collate findings at each level and exploit the accurate definition of both human and murine phenotypes now possible.

Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses. This study sought to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers. Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing. Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers. Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.

Kongenitale und andere Myopathien

The myopathies presented here fall into two groups: Congenital myopathies and protein aggregate myopathies. These genetic conditions often require all modern diagnostic investigations, including histology, enzyme histochemistry, immunohistochemistry and electron microscopy to pave the way to an adequate individual molecular analysis and diagnosis. This is necessary to provide the patient and his or her family information about disease-characteristics or even disease-specific features. Distal myopathies, although caused by mutations in different genes, and toxic myopathies as acquired neuromuscular conditions largely provide non-specific morphological features a correct nosological interpretation of which only succeeds with additional non-morphological data.

From ectodermal dysplasia to selective tooth agenesis

The history and the lessons learned from hypohidrotic ectodermal dysplasia (HED) may serve as an example for the unraveling of the cause and pathogenesis of other ectodermal dysplasia syndromes by demonstrating that phenotypically identical syndromes (HED) can be caused by mutations in different genes (EDA, EDAR, EDARADD), that mutations in the same gene (EDA) can lead to different phenotypes (HED and selective tooth agenesis) and that mutations in genes further downstream in the same signaling pathway (NEMO) may modify the phenotype quite profoundly (incontinentia pigmenti (IP) and HED with immunodeficiency). But it also demonstrates that diligent phenotype characterization and classification is extremely helpful in uncovering the underlying genotype. We also present a new mutation in the EDA gene which causes selective tooth agenesis and demonstrates the phenotype variation that can be encountered in the ectodermal dysplasia syndrome (HED) with the highest prevalence worldwide.

Knockdown of alpha myosin heavy chain disrupts the cytoskeleton and leads to multiple defects during chick cardiogenesis

Atrial septal defects are a common congenital heart defect in humans. Although mutations in different genes are now frequently being described, little is known about the processes and mechanisms behind the early stages of atrial septal development. By utilizing morpholino-induced knockdown in the chick we have analysed the role of alpha myosin heavy chain during early cardiogenesis in a temporal manner. Upon knockdown of alpha myosin heavy chain, three different phenotypes of the atrial septum were observed: (1) the atrial septum failed to initiate, (2) the septum was initiated but was growth restricted, or (3) incorrect specification occurred resulting in multiple septa forming. In addition, at a lower frequency, decreased alpha myosin heavy chain was found to give rise to an abnormally looped heart or an enlarged heart. Staining of the actin cytoskeleton indicated that many of the myofibrils in the knockdown hearts were not as mature as those observed in the controls, suggesting a mechanism for the defects seen. Therefore, these data suggest a role for alpha myosin heavy chain in modelling of the early heart and the range of defects to the atrial septum suggest roles in its initiation, specification and growth during development.

M1993 Clinicopathological Features and Prognostic Factors of Proximal Gastric Carcinoma in High H. pylori Prevalence Country; a Single Center, Large Volume Experience

Introduction: Gastric carcinogenesis is a multistep process including mutation of different genes as well as epigenetic events as aberrant promotor methylation leading to gene silencing. Morphologically, disease progression appears as a sequence of intestinal metaplasia dysplasia invasive carcinoma, triggered by Helicobacter pylori (HP) infection. Methylation of the Estrogen receptor (ER) promotor has been attributed to the development of colorectal cancer and esophageal adenocarcinoma. Its role in gastric carcinogenesis has remained so far elusive. Methods: To study Estrogen promotor methylation patterns along the carcinogenesis pathway in the stomach, we examined gastric mucosa in different conditions by qunatitative methylation specific PCR (rt-MSP). We tested samples from 8 newborns, 49 individuals who underwent endoscopy due to dyspepsia and 8 cases with intestinal metaplasia, as well as from 30 individuals with gastric cancer. PCR specimen were analysed blind and later correlated with histopathological findings. Results: None of the 8 newborns showed a positive rt-MSP results. From the 49 individuals examined, 27 had histologically normal gastric mucosa (13/49) or Helicobacter pylori negative gastritis (14/49). Three specimen of this population showed positive rt-MSP results (11%). On the other hand all individuals with H. pylori positive gastritis (22/49) showed ER promotor methylation (100%). Furthermore, 8 specimen from gastric intestinal metaplasia and 30 samples from gastric cancer tested positive for ER promotor methylation. The correleation of ER promotor methylation with H. pylori gastritis, intestinal metaplasia and gastric carcinoma was highly significant. Discussion: ER promoter methylation has been reported in the context of esophageal and colon carcinogenesis. Here we demonstrate that this epigenetic event is not tumor specific but already present in precancerous lesions of gastric cancer, as early as HP positive gastritis. This data suggest that ER promoter methylation might play a role in the early steps of gastric carcinogenesis and possibly can identify individuals at risk for this highly prevalent tumor.

Medullary sponge kidney associated with primary distal renal tubular acidosis and mutations of the H+-ATPase genes

Medullary sponge kidney (MSK) is a rare congenital disease characterized by diffuse ectasia or dilation of precalyceal collecting tubules. Although its pathogenesis is unknown, the association with various congenital diseases suggests that it could be a developmental disorder. In addition to the typical clinical features of nephrocalcinosis and urolithiasis, patients with MSK show tubular function defects of acidification and concentration. These are considered to be secondary to morphological changes of collecting tubules. Primary distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H(+) ions in the intercalated cells of the collecting duct required for final excretion of fixed acids. Both autosomal dominant and autosomal recessive forms have been described, the latter is also associated with sensorineural hearing loss. We report two patients presenting with dRTA, late sensorineural hearing loss and MSK, in whom molecular investigations demonstrated the presence of mutations of the H(+) proton pump ATP6V1B1 and ATP6V0A4 genes. These observations, including a previous description of a similar case in the literature, indicate that MSK could be a consequence of the proton pump defect, thus can potentially provide new insights into the pathogenesis of MSK.

Specific podocin mutations determine age of onset of nephrotic syndrome all the way into adult life

In steroid-resistant nephrotic syndrome (SRNS) Machuca et al. report that mutations of the recessive podocin gene cause adult-onset SRNS if the R229Q genetic variant occurs in a compound heterozygous state with another podocin mutation. Learning to tell apart the specific allele combinations of podocin mutations will be important for prognosis, genetic counseling in living related kidney donation, accurate etiologic classification within treatment studies, and the understanding of podocin function.