USH1A: chronicle of a slow death.
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Amino Acid Sequence↗
Biomedical subjects
Arnold Munnich
Publications and source records attributed to Arnold Munnich.
TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd.
Activation of the NF-kappaB pathway by the TNF-receptor Edar (Ectodysplasin receptor) and its downstream adaptator Edaradd (Edar-associated death domain) is essential for the development of hair follicles, teeth, exocrine glands and other ectodermal derivatives. Dysfunction of Edar signalling causes hypohidrotic/anhidrotic ectodermal dysplasia (ED), a disorder characterized by sparse hair, lack of sweat glands and malformation of teeth. The Edar signalling pathway stimulates NF-kappaB transcription factors via an activation of the IkappaB kinase (IKK) complex. To gain further insight into the mechanism of IKK activation by Edar and Edaradd, we performed a yeast two-hybrid screen and isolated TAB2 (TAK1-binding protein 2) as a binding partner of Edaradd. TAB2 is an adaptator protein that brigdes TRAF6 (TNF-receptor-associated factor 6) to TAK1 (TGFbeta-activated kinase 1), allowing TAK1 activation and subsequent IKK activation. Here, we show that endogenous and overexpressed TAB2, TRAF6 and TAK1 co-immunoprecipitated with Edaradd in 293 cells. Moreover, we show that dominant negative forms of TAB2, TRAF6 and TAK1 blocked the NF-kappaB activation induced by Edaradd. These results support the involvement of the TAB2/TRAF6/TAK1 signalling complex in the Edar signal transduction pathway and have important implications for our understanding of NF-kappaB activation and EDs in human.
Adaptor Proteins, Signal Transducing↗
Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction.
Heterozygous mutations of the PHOX2B gene account for a broad variety of disorders of the autonomic nervous system, either isolated or combined, including congenital central hypoventilation syndrome (CCHS), tumours of the sympathetic nervous system and Hirschsprung disease. In CCHS, the prevalent mutation is an expansion of a 20-alanine stretch ranging from +5 to +13 alanines, whereas frameshift and missense mutations are found occasionally. To determine the molecular basis of impaired PHOX2B function, we assayed the transactivation and DNA binding properties of wild-type and mutant PHOX2B proteins. Furthermore, we investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. We found that transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. Such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations. However, additional mechanisms such as toxic gain-of-function may play a role in the pathogenic process.
Animals↗
Identification of mutations in CUL7 in 3-M syndrome.
Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion. Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.
Carrier Proteins↗
Exclusion of WNT4 as a major gene in Rokitansky-Küster-Hauser anomaly.
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Abnormalities, Multiple↗
Clinical and molecular overlap in overgrowth syndromes.
Here, we report the clinical and molecular analysis of 75 patients with overgrowth and mental retardation, including 45 previously reported cases [Rio et al., 2003; Baujat et al., 2004]. Two groups are distinguished: group I corresponding to patients with recognizable overgrowth syndromes (Sotos syndrome (SS), Weaver syndrome (WS), Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome (SGBS), and del(22)(qter) syndrome) (60 cases) and group II corresponding to unclassified cases (15 patients). We investigated NSD1 and GPC3 deletions or mutations, 11p15 abnormalities, and 22qter deletions. Surprisingly, in Group I, two SS patients had 11p15 abnormalities and two patients with Beckwith-Wiedemann syndrome had NSD1 aberrations. In group II, two cases of del(22)(qter) were identified but neither NSD1, 11p15, nor GPC3 abnormalities were detected. These results emphasize the clinical and molecular overlap in overgrowth conditions.
Beckwith-Wiedemann Syndrome↗
Monolysocardiolipins accumulate in Barth syndrome but do not lead to enhanced apoptosis.
Barth syndrome (BTHS) is an X-linked recessive disorder that is biochemically characterized by low cellular levels of the mitochondrial phospholipid cardiolipin (CL). Previously, we discovered that the yeast disruptant of the TAZ ortholog in Saccharomyces cerevisiae not only displays CL deficiency but also accumulates monolysocardiolipins (MLCLs), which are intermediates in CL remodeling. Therefore, we set out to investigate whether MLCL accumulation also occurs in BTHS. Indeed, we observed MLCL accumulation in heart, muscle, lymphocytes, and cultured lymphoblasts of BTHS patients; however, only very low levels of these lysophospholipids were found in platelets and fibroblasts of these patients. Although the fatty acid composition of the MLCLs was different depending on the tissue source, it did parallel the fatty acid composition of the (remaining) CLs. The possible implications of these findings for the two reported CL remodeling mechanisms, transacylation and deacylation/reacylation, are discussed. Because MLCLs have been proposed to be involved in the initiation of apoptosome-mediated cell death by the sequestration of the proapoptotic protein (t)BH3-interacting domain death agonist (Bid) to the mitochondrial membrane, we used control and BTHS lymphoblasts to investigate whether the accumulation of MLCLs results in higher levels of apoptosis. We found no differences in susceptibility to death receptor-mediated apoptosis or in cellular distribution of Bid, cytochrome c, and other parameters, implying that MLCL accumulation does not lead to enhanced apoptosis in cultured BTHS lymphoblasts.
Acylation↗
Intrafamilial phenotypic variability of osteopetrosis due to chloride channel 7 (CLCN7) mutations.
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Chloride Channels↗
Mutation in myosin heavy chain 6 causes atrial septal defect.
Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain. The cardiac transcription factor TBX5 strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome, do not. Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation. These data provide evidence for a link between a transcription factor, a structural protein and congenital heart disease.
Adult↗
Respiratory chain deficiency presenting as congenital nephrotic syndrome.
Nephrotic syndrome (NS) in infancy includes NS of Finnish type (mutation of the nephrin gene), diffuse mesangial sclerosis (idiopathic or linked to WT1 mutation), idiopathic NS, most often steroid resistant, and NS related to infections during pregnancy (virus, syphilis, toxoplasmosis). Later in life, NS has a large variety of etiologies. It has been described in association with neuromuscular symptoms, deafness, and diabetes in a few children and adults with respiratory chain (RC) disorders. To date, however, NS has never been observed in neonates with RC disorders. Here, we report RC deficiency in one infant with certain congenital NS and two siblings with acute neonatal cardiac and renal disease with probable NS. Although clinical and histopathological presentations were initially close to congenital NS of Finnish type, clinical outcome was atypical and nephrin mutation was excluded. Mitochondrial RC complex II+V deficiency was identified in the three patients. Based on these observations, we suggest that RC disorders should be considered in patients with congenital NS.
Biopsy↗
Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome.
Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.
Abnormalities, Multiple↗
PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.
The Phox2b gene is necessary for autonomic nervous-system development. Phox2b-/- mice die in utero with absent autonomic nervous system circuits, since autonomic nervous system neurons either fail to form or degenerate. We first identified the Phox2b human ortholog, PHOX2B, as the gene underlying congenital central hypoventilation syndrome (CCHS, or Ondine curse), with an autosomal dominant mode of inheritance and de novo mutation at the first generation. We have subsequently shown that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous-system development--namely, tumors of the sympathetic nervous system (TSNS), such as neuroblastoma and late-onset central hypoventilation syndrome. Here, we report the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease and/or TSNS. The mutation-detection rate was 92.6% (174/188) in our series, and the most prevalent mutation was an in-frame duplication leading to an expansion of +5 to +13 alanines in the 20-alanine stretch at the carboxy terminal of the protein. Such findings suggest PHOX2B mutation screening as a simple and reliable tool for the diagnosis of CCHS, independent of the clinically variable phenotype. In addition, somatic mosaicism was detected in 4.5% of parents. Most interestingly, analysis of genotype-phenotype interactions strongly supports the contention that patients with CCHS who develop malignant TSNS will harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene. These data further highlight the link between congenital malformations and tumor predisposition when a master gene in development is mutated.
Animals↗
A novel mutation in the GUCY2D gene responsible for an early onset severe RP different from the usual GUCY2D-LCA phenotype.
Patients carrying mutations in the retinal guanylate cyclase (GUCY2D) gene were reported to be constantly affected with a particular form of Leber congenital amaurosis (LCA) defined as a "congenital stationary cone-rod dystrophy with high hypermetropia, panretinal degeneration and highly reduced visual acuity". We report here, the study of two patients affected with different retinal disorder: a typical GUCY2D-LCA phenotype and early-onset severe retinitis pigmentosa (RP). Unexpectedly, they gave birth to an infant suffering from LCA. The genetic study in the family allowed to explain the disease in the infant by showing that the GUCY2D-LCA disease was accounted for by compound heterozygosity for two severe GUCY2D mutations (c.3043+4A>T, c.2943delG) while the early-onset severe RP resulted from homozygosity for a 4 bp insertion in the same gene, despite the sound phenotypic differences (c.3236insACCA). Interestingly, this last mutation is excepted to result in a 28 amino acid elongation of the protein contrary to all GUCY2D mutations accounting for LCA which are expected to be null alleles. This report gives support to the existence of exceptional GUCY2D mutations accounting for a milder and different phenotype compared to the typical GUCY2D congenital stationary cone-rod dystrophy.
Adolescent↗
A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency.
The alpha-ketoglutarate dehydrogenase complex (KGDC) catalyses the decarboxylation of alpha-ketoglutarate into succinyl-coenzyme A in the Krebs cycle. This enzymatic complex is made up of three subunits (E1, encoded by PDHA1; E2, encoded by DLST; and E3, encoded by DLD). The E3 subunit is common to two other enzymatic complexes, namely pyruvate dehydrogenase complex (PDC) and branched-chain ketoacid dehydrogenase complex (BCKDC). KGDC deficiency is a rare autosomal recessive disorder, most often presenting with severe encephalopathy and hyperlactatemia with neonatal onset. We found a KGDC deficiency in cultured skin fibroblasts from three siblings born to consanguinous parents. E3 subunit activity was shown to be deficient (20% of control values), despite the absence of usual clinical clues to E3 deficiency, i.e. accumulation of pyruvate and branched-chain amino acids in plasma and branched-chain alpha-ketoacids in urine. RT-PCR of E3 mRNA from the three patients, followed by sequencing, revealed an homozygous c.1444A>G substitution located in E3 exon 13, predictive of a p.R482G (or R447G in the processed gene product) substitution in a highly conserved domain of the protein. Only eleven E3 mutations have been reported so far. The only other case of E3 deficiency without clinical or biochemical evidences of PDC and BCKDC deficiencies has been ascribed to a c.1436A>T (p.D479V; or D444V in the processed gene product) mutation, very close to the mutation reported herein. Since c.1444A>G (p.R482G; or R447G in the processed gene product) and c.1436A>T (p.D479V; or D444V in the processed gene product) lie within the interface domain of E3 with E2 (KGDC and BCKDC) or the E3-binding protein (PDC), our data suggest that interaction of E3 with these other subunits differs in some extent among KGDC, PDC, and BCKDC.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Improved single-cell protocol for preimplantation genetic diagnosis of spinal muscular atrophy.
OBJECTIVE: To develop and validate a simple and reliable single-cell analysis protocol for the preimplantation genetic diagnosis (PGD) of spinal muscular atrophy (SMA). DESIGN: Molecular tests based on specific enzymatic digestion have already been described for SMA diagnosis. We modified the amplified DNA fragments so as to introduce a novel restriction site that provides an internal control for the completeness of the digestion. SETTING: The genetics and reproduction departments of two teaching hospitals. PATIENT(S): Six informed couples at risk of transmitting SMA. INTERVENTION(S): All patients underwent standard procedures associated with intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Improvement of SMA diagnostic efficiency and accuracy on single cell. RESULT(S): One hundred fifty lymphocytes were analyzed with our protocol. One hundred percent diagnostic accuracy was achieved from both homozygous normal and SMN1-deleted leukocytes. Successful molecular analysis was achieved for 36 of 42 biopsied embryos (86%). Twenty-five normal embryos were transferred, but no pregnancy was achieved. CONCLUSION(S): We developed an improved protocol for PGD of SMA that is simple, robust, and accurate; unfortunately, no pregnancies were achieved for any of the six patients who have undergone PGD in the program thus far.
Base Sequence↗
Exclusion of the dymeclin and PAPSS2 genes in a novel form of spondyloepimetaphyseal dysplasia and mental retardation.
Spondyloepimetaphyseal dysplasias (SEMD) represent a heterogeneous group of conditions composed of at least 15 well-defined entities. The classification is based on clinical, radiological and molecular findings. Among them, several conditions also include a mental retardation (MR) syndrome, namely Wolcott-Rallison syndrome, Dyggve-Melchior-Clausen syndrome (DMC) and lysosomal storage disorders. Here, we report on a novel form of SEMD with MR in two Pakistani sisters born to first-cousin parents. SEMD, MR, microcephaly, ataxia, facial dysmorphism and hirsutism of back and legs were noted in the two children. Skeletal findings included flat vertebral bodies with irregular vertebral plates, irregular and flared metaphyses with vertical striations, small and irregular epiphyses, small carpal bones and narrow iliac wings without lacy pelvis iliac crest. Similarities with DMC prompted us to test and eventually exclude the DMC gene, dymeclin, by direct sequencing. Similarly, we excluded the PAPSS2 gene (3'-alpha phosphoadenosine 5'-phosphosulphate synthase 2) responsible for SEMD Pakistani type. The combination of features observed in the two sisters does not fit with any previously reported SEMD and represents therefore a novel form of autosomal recessive SEMD with MR.
Abnormalities, Multiple↗
Failure to detect an 8p22-8p23.1 duplication in patients with Kabuki (Niikawa-Kuroki) syndrome.
Kabuki syndrome (KS) is a rare MCA/MR syndrome with an estimated frequency of 1/32 000 in Japan. This syndrome is characterized by postnatal growth retardation, distinctive facial features, dermatoglyphic anomalies, skeletal dysplasia, and mental retardation. The molecular basis of KS remains unknown. Recently, Milunsky and Huang reported on six unrelated patients with a clinical diagnosis of KS and an 8p22-8p23.1 duplication using comparative genomic hybridization and BAC-FISH studies. Also, they suggested that a paracentric inversion may contribute to the occurrence of KS. In the present study, 24 patients with a clinical diagnosis of KS based on Niikawa-Kuroki criteria have been collected. They were tested for the presence of an 8p duplication using the same clones as described by Milunsky and Huang. Our results do not confirm the previously described association between KS and an 8p22-8p23.1 duplication.
Abnormalities, Multiple↗
Functional disomy of the Xq28 chromosome region.
We report on two patients, a boy and a girl, with an additional Xq28 chromosome segment translocated onto the long arm of an autosome. The karyotypes were 46,XY,der(10)t(X;10)(q28;qter) and 46,XX,der(4)t(X;4)(q28;q34), respectively. In both cases, the de novo cryptic unbalanced X-autosome translocation resulted in a Xq28 chromosome functional disomy. To our knowledge, at least 17 patients with a distal Xq chromosome functional disomy have been described in the literature. This is the third report of a girl with an unbalanced translocation yielding such a disomy. When the clinical features of both patients are compared to those observed in patients reported in the literature, a distinct phenotype emerges including severe mental retardation, facial dysmorphic features with a wide face, a small mouth and a thin pointed nose, major axial hypotonia, severe feeding problems and proneness to infections. A clinically oriented FISH study using subtelomeric probes is necessary to detect such a cryptic rearrangement.
Abnormalities, Multiple↗