Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class II nonmuscle myosin heavy chains

Nonmuscle myosin heavy chain II-A is responsible for MYH9-related disease, which is characterized by macrothrombocytopenia, granulocyte inclusions, deafness, cataracts, and renal failure. Since another two highly conserved nonmuscle myosins, II-B and II-C, are known, an analysis of their tissue distribution is fundamental for the understanding of their biological roles. In mouse, we found that all forms are ubiquitously expressed. However, megakaryocytic and granulocytic lineages express only II-A, suggesting that congenital features, macrothrombocytopenia, and leukocyte inclusions correlate with its exclusive presence. In kidney, eye, and ear, where clinical manifestations have a late onset, as well as in other tissues apparently not affected in patients, II-A and at least one of the other two isoforms are expressed, suggesting that II-B and II-C can partially compensate for each other. We hypothesize that cells expressing only II-A manifest the congenital defects, while tissues expressing additional myosin II isoforms show either late onset of abnormalities or no pathological sign.     

Epstein syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene

Epstein syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA ( MYH9). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "D?hle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.     

Genome wide analysis in a family with sensorineural hearing loss,autism and mental retardation

Hearing loss is a common congenital anomaly with an incidence of 1 in 1000 live births. It has been described together with several other clinical features as fortuitous association or commune genetic syndrome. In this study, we investigated a consanguineous Tunisian family with moderate to profound congenital hearing loss, mental retardation and autistic behaviors. We performed a genome wide microarray analysis study using approximately 300,000 SNPs in a common set of 7 invidious of this family. We identified regions of suggestive linkage with hearing loss on chromosomes 6p12 and 7q34. In addition, we identified a deletion on chromosome 8p in the two autistic individuals. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family. The application of next generation sequencing for this family seems to be a good strategy for further analysis leading to the identification of candidate genes.     

Fryns syndrome without diaphragmatic hernia. Report on a new case and review of the literature

Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by coarse facies, diaphragmatic hernia, distal limb hypoplasia and malformations of the cardiovascular, gastrointestinal, genitourinary and central nervous systems. Diaphragmatic hernia is a leading diagnostic feature in Fryns syndrome, recorded in more than 80% of cases. We report a newborn with clinical features of Fryns syndrome except the diaphragmatic hernia. Cases of Fryns syndrome without diaphragmatic hernia are reviewed. Even in the absence of diaphragmatic hernia, pulmonary anomalies are described in Fryns syndrome, especially pulmonary hypoplasia. Fetal mice, exposed to nitrofen, have a high incidence of congenital diaphragmatic hernia and other malformations similar to that seen in Fryns syndrome. Nitrofen might target molecular mechanisms similar to those involved in Fryns syndrome.     

Warburg micro syndrome in two children from a highly inbred Turkish family

Warburg Micro syndrome (WMS) was first reported by Warburg in 1993. The cardinal features are microcephaly, microphthalmia, congenital cataract and intellectual disability. We report on two children from a highly inbred family with microcephaly, congenital cataract, optic atrophy, hypotonia and severe psychomotor retardation. This phenotype is similar to other reported rare entities and especially to the family reported by Warburg. Four other children in the same family may also have been affected. In this report, the symptoms and features of our cases are compared with the Warburg Micro syndrome patients in literature.     

A molecular defect in intracellular lipid signaling in human neutrophils in localized aggressive periodontal tissue damage

Host defense mechanisms are impaired in patients with congenital neutrophil (polymorphonuclear neutrophils (PMN)) defects. Impaired PMN chemotaxis is observed in localized aggressive periodontitis (LAP), a familial disorder characterized by destruction of the supporting structures of dentition. In the present studies, we sought evidence for molecular events underlying this aberrant human PMN phenotype. To this end, PMN transendothelial migration and superoxide anion generation were assessed with LAP patients and asymptomatic family members, as well as patients with other chronic mucosal inflammation. PMN from LAP patients showed decreased transmigration across vascular endothelial monolayers (18 +/- 12% of control, n = 4) and increased superoxide anion generation (358 +/- 37%, p = 0.003). Gene expression was analyzed using oligonucleotide microarrays and fluorescence-based kinetic PCR. cDNA microarray and kinetic-PCR analysis revealed diminished RNA expression of leukocyte-type diacylglycerol (DAG) kinase alpha in PMN from LAP patients (4.6 +/- 1.7 relative units, n = 6, p = 0.007) compared with asymptomatic individuals (51 +/- 27 relative units, n = 7). DAG kinase activity was monitored by DAG phosphorylation and individual DAG molecular species were quantified using liquid chromatography and tandem mass spectrometry-based lipidomics. DAG kinase activity was also significantly decreased (73 +/- 2%, p = 0.007) and correlated with increased accumulation of 1,2-diacyl-sn-3-glycerol substrates (p = 0.01). These results implicate defects in both PMN transendothelial migration and PMN DAG kinase alpha signaling as disordered functions in LAP. Moreover, they identify a potential molecular lesion in PMN signal transduction that may account for their aberrant responses and tissue destruction in this disease.     

Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes

May-Hegglin anomaly (MHA) and Fechtner (FTNS) and Sebastian (SBS) syndromes are autosomal dominant platelet disorders that share macrothrombocytopenia and characteristic leukocyte inclusions. FTNS has the additional clinical features of nephritis, deafness, and cataracts. Previously, mutations in the nonmuscle myosin heavy chain 9 gene (MYH9), which encodes nonmuscle myosin heavy chain IIA (MYHIIA), were identified in all three disorders. The spectrum of mutations and the genotype-phenotype and structure-function relationships in a large cohort of affected individuals (n=27) has now been examined. Moreover, it is demonstrated that MYH9 mutations also result in two other FTNS-like macrothrombocytopenia syndromes: Epstein syndrome (EPS) and Alport syndrome with macrothrombocytopenia (APSM). In all five disorders, MYH9 mutations were identified in 20/27 (74%) affected individuals. Four mutations, R702C, D1424N, E1841K, and R1933X, were most frequent. R702C and R702H mutations were only associated with FTNS, EPS, or APSM, thus defining a region of MYHIIA critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness. The E1841K, D1424N, and R1933X coiled-coil domain mutations were common to both MHA and FTNS. Haplotype analysis using three novel microsatellite markers revealed that three E1841K carriers--one with MHA and two with FTNS--shared a common haplotype around the MYH9 gene, suggesting a common ancestor. The two new globular-head mutations, K371N and R702H, as well as the recently identified MYH9 mutation, R705H, which results in DFNA17, were modeled on the basis of X-ray crystallographic data. Altogether, our data suggest that MHA, SBS, FTNS, EPS, and APSM comprise a phenotypic spectrum of disorders, all caused by MYH9 mutations. On the basis of our genetic analyses, the name "MYHIIA syndrome" is proposed to encompass all of these disorders.     

Report of a girl with Klippel-feil syndrome and Poland anomaly

Report of a girl with Klippel-feil syndrome and Poland anomaly: Klippel-Feil syndrome, consisting of the triad of a short neck, low posterior hairline, and limitation of neck movement, is a congenital anomaly characterized by the fusion of cervical vertebrae, Poland anomaly consists of unilateral aplasia of the chest wall muscles and ipsilateral anomalies of upper extremity. We report a 7-year-old girl with typical findings of Klippel-Feil syndrome and Poland anomaly. To the best of our knowledge a case of Klippel-Feil syndrome and Poland anomaly has not been described before, although a combination of Poland, Klippel-Feil and Moebius anomalies has been reported in the literature.     

Heat-induced oligomerization of gp96 occurs via a site distinct from substrate binding and is regulated by ATP

Among three different isoforms of non-muscle myosin heavy chains (NMMHCs), only NMMHCA is associated with inherited human disease, called MYH9 disorders, characterized by macrothrombocytopenia and characteristic granulocyte inclusions. Here targeted gene disruption was performed to understand fundamental as well as pathological role of the gene for NMMHCA, MYH9. Heterozygous intercrosses yielded no homozygous animals among 552 births, suggesting that MYH9 expression is required for embryonic development. In contrast, MYH9+/- mice were viable and fertile without gross anatomical, hematological, and nephrological abnormalities. Immunofluorescence analysis also showed the normal cytoplasmic distribution of NMMHCA. We further measured the auditory brainstem response and found two of six MYH9+/- mice had hearing losses, whereas the remaining four were comparable to wild-type mice. Such observation may parallel the diverse expression of Alport's manifestations of human individuals with MYH9 disorders and suggest the limited requirement of the gene for maintenance and function of specific organs.     

The Opitz hypertelorism-hypospadias syndrome. Further delineation of the spectrum of clinical findings

In this paper we report three male patients with the Opitz hypertelorism-hypospadias syndrome. In addition to the typical morphological findings, signs of cerebral palsy related to dysmaturity and perinatal adaptation problems were present in two of them. This illustrates that this syndrome is a true multiple congenital anomaly/mental retardation MCA/MR syndrome with great variability in expression of clinical symptoms.     

Morphological, ultrastructural, cytochemical and functional analysis of neutrophils deficient in myeloperoxidase

Eighteen patients with established hereditary myeloperoxidase deficiency underwent morphological, ultrastructural, cytochemical and functional analysis in order to correlate the lack of peroxidase from phagocytes with other leucocyte activities. Cytochemical and ultrastructural findings only confirmed the peroxidase defect in neutrophil and monocyte population, whereas normal peroxidase activity was detected in eosinophil granulocytes ("Alius-Grignaschi anomaly"). Morphological analysis, as determined by both ligh and electron microscopy, showed in two patients with total MPO-deficiency a large number of neutrophils (50-60%) with nuclear abnormalities very similar to Pelger-Huet's heterozygous form (two lobed neutrophils having a typical pince-nez appearance and a nuclear chromatin coarser than that of normal PMNL). Other 2 cases displayed a 50-60% five-lobed neutrophils, as occur in congenital nuclear hypersegmentation of PMNL. These findings suggest that Alius-Grignaschi anomaly and Pelger-Huet syndrome can be found associated in the same individuals, since both these abnormalities have a genetic origin. Finally, since an impaired bactericidal and fungicidal activity was observed, no patients displayed particular susceptibility to persistent or severe infections, thus confirming the presence of MPO-independent enzymatic systems.     

A new chromosome anomaly in acute lymphoblastic leukemia (ALL)

Summary A new chromosome anomaly in acute lymphoblastic leukemia (ALL) is reported. Three, possibly four, patients showed an identical karyotype anomaly, characterized by a (4;11)(q13;q22) reciprocal translocation. This anomaly has not so far been found in lymphoproliferative disorders other than ALL. Two of the patients had congenital leukemia, but the anomaly described appears to be more characteristic of ALL than of congenital leukemia, and may help the clinician in establishing the diagnosis of ALL.     

Phenotypic correlations in a patient with ring chromosome 22

Ring chromosome 22, a rare cytogenetic anomaly, has been described in over 60 cases in the medical literature. The aim of this report was to present a case carrying ring chromosome 22, and her family.It is a case report of a patient presented at Medical Faculty of ?ukurova University in Turkey.An 8-year-old girl with ring chromosome 22 and her family were evaluated cytogenetically and clinically.A chromosome analysis of the proband revealed a de novo 46, XX, r(22)(p11.2;q13) karyotype. Our subject demonstrated the prominent features of this syndrome including profound mental retardation, language impairment, dysmorphic features, lack of speech, hyperactivity, and behavioral disorders.There is lack of consistency between the physical abnormalities that we observed in our subject and those observed for such patients in the literature. The wide range of manifestations observed in patients with this cytogenetic alteration is probably due to size differences in the deleted region.     

Solution structure of the BRK domains from CHD7

CHD7 is a member of the chromodomain helicase DNA binding domain (CHD) family of ATP-dependent chromatin remodelling enzymes. It is mutated in CHARGE syndrome, a multiple congenital anomaly condition. CHD7 is one of a subset of CHD proteins, unique to metazoans that contain the BRK domain, a protein module also found in the Brahma/BRG1 family of helicases. We describe here the NMR solution structure of the two BRK domains of CHD7. Each domain has a compact betabetaalphabeta fold. The second domain has a C-terminal extension consisting of two additional helices. The structure differs from those of other domains present in chromatin-associated proteins.     

Congenital anonychia and brachydactyly of the left foot - Cooks syndrome variant: Case report and review of literature

Cooks syndrome is characterized by familial congenital anonychia or onychodystrophy, hypoplasia or absence of distal phalanges of the hands and feet with brachydactyly of the fifth finger and digitalization of the thumb (triphalangism). It is listed as a “rare disease” by the Office of Rare Diseases of the National Institutes of Health. Here, we report a case of congenital anonychia and brachydactyly of the left foot, which possibly is a variant of Cooks syndrome with a positive family history of similar deformity.     

Alport's syndrome in twins]

Alport's syndrome consists of hereditary nephritis, often progressing to renal failure, and variable neural hearing loss. It was diagnosed in dizygotic twins, aged 32 years, suffering from nephropathy manifested by microscopic hematuria, proteinuria and chronic renal failure, accompanied by hearing loss and ocular disorders (observed in both retina and lenses). Gothic palate has been noted in both patients. Glomerulitis was diagnosed for the first time at the age of 11 and 12 years, respectively. Hearing loss began in one brother 10 years later, and in another 11 years later. Renal failure developed much later. Diagnostic problems were due to the fact, that streptomycin was used in childhood (another cause of hearing loss?) and to the lack of any symptoms of Alport's syndrome in other members of the family.     

Cat eye syndrome and growth hormone deficiency with pituitary anomalies: A case report and review of the literature

Cat eye syndrome is a rare congenital disease characterized by the existence of a supernumerary chromosome derived from chromosome 22, with a variable phenotype comprising anal atresia, coloboma of the iris and preauricular tags or pits. We report a girl with cat eye syndrome, presenting short stature, with growth hormone deficiency due to posterior pituitary ectopia. Short stature is a common feature of this syndrome, and the association with a structural pituitary anomaly has been described, however growth hormone deficiency and the underlying mechanisms are rarely reported. A review on short stature and growth hormone deficiency in cat eye syndrome is conducted.     

Kallman's syndrome combined with aortic valve anomaly and epilepsy]

Kallman's syndrome is defined clinically as hypogonadotropic hypogonadism associated with anosmia and other congenital abnormalities. There is no report on Kallman's syndrome coexisting with aortic valve anomaly and epilepsy in the available literature. Therefore, the authors considered worthy presenting a case of a 36-years male [correction of female] patient with Kallmann's syndrome combined with aortic valve anomaly, epilepsy and hyperostosis frontalis. Disease history data, clinical examination, the results of hormonal tests and USG helped to establish the diagnosis. Diagnostic and therapeutical problems in such cases have also been discussed.     

Genetic linkage of autosomal-dominant Alport syndrome with leukocyte inclusions and macrothrombocytopenia (Fechtner syndrome) to chromosome 22q11-13

Fechtner syndrome is an autosomal-dominant variant of Alport syndrome, manifested by nephritis, sensorineural hearing loss, cataract formation, macrothrombocytopenia, and polymorphonuclear inclusion bodies. As opposed to autosomal-recessive and X-linked Alport syndromes, which have been genetically well studied, the genetic basis of Fechtner syndrome remains elusive. We have mapped the disease-causing gene to the long arm of chromosome 22 in an extended Israeli family with Fechtner syndrome plus impaired liver functions and hypercholesterolemia in some individuals. Six markers from chromosome 22q yielded a LOD score >3.00. A maximum two-point LOD score of 7.02 was obtained with the marker D22S283 at a recombination fraction of 0. Recombination analysis placed the disease-causing gene in a 5.5-Mb interval between the markers D22S284 and D22S1167. No collagen genes or genes comprising the basement membrane have been mapped to this region.     

CtIP Mutations Cause Seckel and Jawad Syndromes

Seckel syndrome is a recessively inherited dwarfism disorder characterized by microcephaly and a unique head profile. Genetically, it constitutes a heterogeneous condition, with several loci mapped (SCKL1-5) but only three disease genes identified: the ATR, CENPJ, and CEP152 genes that control cellular responses to DNA damage. We previously mapped a Seckel syndrome locus to chromosome 18p11.31-q11.2 (SCKL2). Here, we report two mutations in the CtIP (RBBP8) gene within this locus that result in expression of C-terminally truncated forms of CtIP. We propose that these mutations are the molecular cause of the disease observed in the previously described SCKL2 family and in an additional unrelated family diagnosed with a similar form of congenital microcephaly termed Jawad syndrome. While an exonic frameshift mutation was found in the Jawad family, the SCKL2 family carries a splicing mutation that yields a dominant-negative form of CtIP. Further characterization of cell lines derived from the SCKL2 family revealed defective DNA damage induced formation of single-stranded DNA, a critical co-factor for ATR activation. Accordingly, SCKL2 cells present a lowered apoptopic threshold and hypersensitivity to DNA damage. Notably, over-expression of a comparable truncated CtIP variant in non-Seckel cells recapitulates SCKL2 cellular phenotypes in a dose-dependent manner. This work thus identifies CtIP as a disease gene for Seckel and Jawad syndromes and defines a new type of genetic disease mechanism in which a dominant negative mutation yields a recessively inherited disorder.