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PubMed2024

SLC40A1-related hemochromatosis associated with a p.Y333H mutation in mainland China: a pedigree report and literature review.

BACKGROUND: Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete. CASE PRESENTATION: We report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin. CONCLUSIONS: This study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.

Humans↗
PubMed2005

Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy.

Closure of ATP-sensitive K(+) channels (K(ATP) channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic beta-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in approximately 47% of patients diagnosed with permanent diabetes at <6 months of age. There is a striking genotype-phenotype relationship with specific Kir6.2 mutations being associated with transient neonatal diabetes, permanent neonatal diabetes alone, and a novel syndrome characterized by developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. All mutations appear to cause neonatal diabetes by reducing K(ATP) channel ATP sensitivity and increasing the K(ATP) current, which inhibits beta-cell electrical activity and insulin secretion. The severity of the clinical symptoms is reflected in the ATP sensitivity of heterozygous channels in vitro with wild type > transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated K(ATP) channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the K(ATP) channel.

Diabetes Mellitus, Type 1↗
PubMed1999

Genetic analysis of mouse-adapted influenza A virus identifies roles for the NA, PB1, and PB2 genes in virulence.

Adaptation of the prototype A/FM/1/47 H1N1 strain to mice resulted in selection of the A/FM/1/47-MA variant with increased virulence. Earlier analysis identified mutations in the HA and M1 genes that increase virulence in the mouse. Complete sequence analysis identified mutations in the PB1, PB2, HA, NA, and M1 genes. Reassortants were produced between the parental FM and FM-MA strains to obtain viruses that differ due to combinations of mutant genes. To assess the relationship between virulence and replication, the median lethal dose was determined for mice and growth properties were assessed in mouse lung, MDCK cells and chicken embryo. Not only were all five mutations shown to control virulence but also the replicative capacity in the mouse. The HA, NA and M1 mutations increased yield in all three hosts whereas in combination the PB1 and PB2 mutations were host restrictive changing the virus to a mouse specific strain. For the NA and M1 mutations the increase in growth in mouse lung was proportional to a 2-fold (log10) increase in virulence however the HA mutation increased virulence largely independent of increased growth indicating a change in pathological properties that damage the host. Thus mutations that affect virulence can be classified according to host-dependent and independent ability to increase growth as well as changes in pathological properties. Each of the PB1, PB2, NA, HA, and M1 genes acquired gain-of-function mutations for mouse infection that involve structural motifs that may serve as markers for virulence or targets for antiviral therapy.

Adaptation, Physiological↗
PubMed2006

Unsupervised analysis uncovers changes in histopathologic diagnosis in supervised genomic studies.

Human gastrointestinal stromal tumors (GIST) have recently emerged as a distinct mesenchymal tumor type that has a unique phenotype characterized by a gain of function mutations in c-kit. In contrast, leiomyosarcomas (LMS) of the gastrointestinal tract or retroperitoneum, which were previously classified together with GISTs as gastrointestinal sarcomas, have much less frequent mutations of c-kit. We performed microarray analyses to gain a comprehensive understanding of the difference between the two types of soft-tissue sarcomas at the level of gene expression. Microarray experiments were performed on 30 GISTs and 30 LMSs that were collected at the time of surgical resection. These tumors were categorized based on the histopathologic diagnosis recorded in our institutional database. Prior to our search for genes that are differentially expressed between these two types of cancers, we first carried out an unsupervised analysis using multidimensional scaling (MDS) to determine whether the two groups have marked overall differences in gene expression. Initially, the MDS did not reveal a good separation between the two groups. We then re-reviewed the histopathology of these tumors and realized that some of the cases included in our study were acquired 10 years ago when the diagnosis of gastrointestinal sarcoma was made according to histopathologic criteria alone without immunohistochemistry for c-kit. An experienced pathologist reviewed all of the specimens and this revealed that a number of the GIST cases were classified as LMS in the clinical database. Correction of the histopathologic diagnosis and relabeling of the samples resulted in a much more pronounced separation of GIST and LMS in the MDS analysis. This study underscores the need to re-review histopathology as reclassification occurs. While updating the clinical database may be desired, this is usually impractical. For molecular studies that use archival samples, it is critical to have the archival samples re-reviewed by a pathologist. Further, unsupervised analysis often proves to be a critical quality control step in identifying structural problems that may exist. Finally, MDS analysis further supports that GIST is a distinct type of sarcoma.

Biomarkers, Tumor↗
PubMed1999

A novel luteinizing hormone receptor mutation in a patient with familial male-limited precocious puberty: effect of the size of a critical amino acid on receptor activity.

Familial male-limited precocious puberty (FMPP) is a form of luteinizing hormone-releasing hormone (LHRH)-independent isosexual precocious puberty caused by gain-of-function mutations of the luteinizing hormone/chorionic gonadotropin receptor (hLHR). The most common mutation is 1733 A>G, which causes substitution of Asp-578 by Gly. In this study, a male infant presented at the age of 20 months with accelerated sexual development was analyzed for the presence of activating mutations of the hLHR. Analysis of exon 11 of the hLHR gene by genomic polymerase chain reaction (PCR), asymmetric PCR, and dideoxy sequencing identified a single base substitution, 1734 T>A, which led to the replacement of Asp-578 by Glu. The same mutation was found in the mother. Expression of the mutated hLHR in HEK 293 cells demonstrated elevated basal levels of intracellular cAMP in the transfected cells confirming the constitutive activating nature of the mutated hLHR. A possible genotype-phenotype relationship of the hLHR mutations was examined by a comparison of the in vitro activities of the hLHRs carrying the Asp578Gly, Asp578Tyr, Asp578Trp, and Asp578Glu mutations in HEK 293 cells. A positive correlation between the size of the substituting amino acid and the basal level of intracellular cAMP of cells expressing the mutated receptor was demonstrated.

Amino Acid Sequence↗
PubMed2004

c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue).

Extragastrointestinal stromal tumor (EGIST) is a unique tumor that occurs outside the gastrointestinal tract. EGIST shows a c-kit expression and histologic appearance similar to those of gastrointestinal stromal tumor (GIST). Most GISTs have gain-of-functional mutation of the c-kit gene, and some have mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. However, the frequency of mutation of those genes in EGISTs remains unclear. We examined the clinicopathologic features, prognostic factors, and c-kit and PDGFRA mutation in 39 cases of EGIST. Tumors with high mitotic counts (>or=5/50 high power fields) or a high Ki-67 labeling index (>or=10%) were significantly correlated with worse prognoses. The c-kit mutation was found in the juxtamembrane domain (exon 11) and the extracellular domain (exon 9) in 12 of 29 cases (41.4%) and 2 of 29 cases (6.9%), respectively. The PDGFRA gene mutation was found at the juxtamembrane domain (exon 12) and the tyrosine kinase domain (exon 18) in one case each. The pattern of kit and PDGFRA mutation in EGIST was essentially similar to that in GIST. Our results suggest that the c-kit and PDGFRA mutations play an important role in the tumorigenesis of EGIST. High mitotic counts and a high Ki-67 labeling index may be useful for predicting the aggressive biologic behavior in EGIST. Furthermore, STI-571, targeting c-kit and PDGFR tyrosine kinase, seems to be a possible therapeutic strategy for EGISTs, especially advanced cases.

Adult↗
PubMed2006

Kit-activating mutations in AML: lessons from PU.1-induced murine erythroleukemia.

In concert with its ligand, the stem cell factor (SCF), the receptor tyrosine kinase c-Kit acts as a key signaling molecule for a number of cell types, including hematopoietic stem cells, mast cells, melanocytes and germ cells. Gain-of-function mutations in c-Kit have been described in a number of human cancers, including testicular germinomas, acute myeloid leukemia and gastrointestinal stromal tumors. Yet their contribution to neoplastic growth is incompletely understood. Now Kosmider et al report the acquisition of Kit mutations in 86% of late-stage eryhtroleukemias in Spi-1/PU.1 transgenic mice. Without Kit mutations, these mice suffer from a benign disease whose hallmark is erythropoietin-dependent expansion of undifferentiated red blood cell precursors. Newly acquired Kit mutations affect codon 814 or 818, and ectopic expression of these mutants in nonmalignant pro-erythroblasts confers erythropoietin independence and tumorigenicity. Using tyrosine kinase inhibitors PP1, PP2, and imatinib mesylate (a.k.a. Gleevac), the authors demonstrate that Kit mutations are important for the autonomous expansion of malignant cells via the MEK/Erk1/2 and PI3K/Akt pathways. These findings validate the notion that one differentiation-blocking (e.g., PU.1 activation) and one proliferative (e.g., c-Kit mutations) event are required for the development of frank leukemia.

Animals↗
PubMed2002

Primosome assembly requirement for replication restart in the Escherichia coli holDG10 replication mutant.

In this report, we study the role of pre-primosome proteins in a strain in which the frequency of replication arrest is increased because of a mutation in a replication protein. The holDG10 mutant was used, in which replication restart involves replication fork reversal. As expected, PriA primosome assembly function is essential for growth of the holDG10 mutant. The priA300 mutation, which inactivates only the helicase function of PriA in vitro, and priB inactivation strongly impair viability. In contrast, priC inactivation has no effect. Therefore, PriB is more important than PriC for PriA-dependent replication fork restart in vivo. The gain of function mutation dnaC809 restores the viability of holDG10 priA and holDG10 priB mutants only to some extent. The dnaC809 820 double mutation restores full viability to the holDG10 mutant lacking either PriA or PriB. Similarly to the holDG10 single mutant, the holDG10 priA dnaC809 820 strain is depend-ent on RecBC for viability, indicating that facilitating primosome assembly using the dnaC809 820 mutation does not allow bypass of replication fork reversal.

Adenosine Triphosphatases↗
PubMed1997

Transgenic animal models of familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) occurs in both sporadic and familial forms, which have very similar clinical presentation and course. Approximately 20% of the familial cases of ALS are caused by mutation of the SODI gene encoding Cu, Zn superoxide dismutase (SOD). Over 30 different SODI gene mutations have been found in patients. Most are missense mutations that cause the substitution of one amino acid for another. The failure to find deletions in familial ALS suggests that the mutant protein is required for pathogenesis. Studies in transgenic mice indicate that familial ALS is caused by gain-of-function mutations in the SODI gene. These enhance formation of free radicals by the mutant enzyme. When expressed at high levels in transgenic mice, mutant human Cu,Zn SOD causes a clinical disease that resembles human ALS. Selective degeneration of motor neurones in the spinal cord and brainstem is accompanied by progressive motor impairment. Pathogenesis in the transgenic model of familial ALS is a sequential, two-step process in which damage mediated by free radicals accumulates to a threshold that triggers catastrophic motor neurone loss through glutamate-mediated, excitotoxic mechanisms. Evidence in support of this hypothesis comes from therapeutic studies with antioxidants and inhibitors of glutamatergic neurotransmission.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Focus on Kir6.2: a key component of the ATP-sensitive potassium channel.

ATP-sensitive potassium (K(ATP)) channels are found in a wide variety of cell types where they couple cell metabolism to electrical activity. In glucose-sensing tissues, these channels respond to fluctuating changes in blood glucose concentration, but in other tissues they are activated only under ischemic conditions or in response to hormonal stimulation. Although K(ATP) channels in different tissues have different regulatory subunits, in almost all cases (except vascular smooth muscle) the pore-forming subunit is the inwardly rectifying K(+) channel Kir6.2. This article reviews recent studies of Kir6.2, focussing on the relation between channel structure and function, and on naturally occurring mutations in Kir6.2 that lead to human disease. New insights into the location of the ATP-binding site, the permeation pathway for K(+), and the gating of the pore provided by homology modelling are discussed in relation to functional studies. Gain-of-function mutations in Kir6.2 cause permanent neonatal diabetes mellitus (PNDM) by reducing the ATP sensitivity of the K(ATP) channel and increasing the K(ATP) current, which is predicted to inhibit beta-cell electrical activity and insulin secretion. Mutations at specific residues, that cause a greater decrease in ATP sensitivity, are associated with additional neurological symptoms. The molecular mechanism underlying the differences in ATP sensitivity produced by these two classes of mutations is discussed. We speculate on how some mutations lead to neurological disease and why no obvious cardiac symptoms are observed. We also consider the implications of these studies for type-2 diabetes.

Adenosine Triphosphate↗
PubMed1994

Novel oncogenic mutations in the WT1 Wilms' tumor suppressor gene: a t(11;22) fuses the Ewing's sarcoma gene, EWS1, to WT1 in desmoplastic small round cell tumor.

These studies suggest that the WT1 tumor suppressor gene, originally identified as a recessive oncogene in Wilms' tumors, is capable of sustaining a gain-of-function mutation which results in its contribution to a completely different disease entity: desmoplastic small round cell tumor. Two independent biochemical functions of WT1, DNA-binding activity and mode of transcriptional regulation, are altered as a consequence of the chromosomal translocation and fusion with EWS. The fusion of EWS and WT1 genes in DSRCT thus provides a unique paradigm for a means by which different alterations of transcription factor function can lead to diverse oncogenic processes.

Amino Acid Sequence↗
PubMed1999

Isolation and characterization of mutations in Bacillus subtilis that allow spore germination in the novel germinant D-alanine.

Bacillus subtilis spores break their metabolic dormancy through a process called germination. Spore germination is triggered by specific molecules called germinants, which are thought to act by binding to and stimulating spore receptors. Three homologous operons, gerA, gerB, and gerK, were previously proposed to encode germinant receptors because inactivating mutations in those genes confer a germinant-specific defect in germination. To more definitely identify genes that encode germinant receptors, we isolated mutants whose spores germinated in the novel germinant D-alanine, because such mutants would likely contain gain-of-function mutations in genes that encoded preexisting germinant receptors. Three independent mutants were isolated, and in each case the mutant phenotype was shown to result from a single dominant mutation in the gerB operon. Two of the mutations altered the gerBA gene, whereas the third affected the gerBB gene. These results suggest that gerBA and gerBB encode components of the germinant receptor. Furthermore, genetic interactions between the wild-type gerB and the mutant gerBA and gerBB alleles suggested that the germinant receptor might be a complex containing GerBA, GerBB, and probably other proteins. Thus, we propose that the gerB operon encodes at least two components of a multicomponent germinant receptor.

Alanine↗
PubMed2005

New treatments for denervating diseases.

There has been considerable recent progress in understanding mechanisms by which gene mutations cause degeneration of motoneurons and peripheral nerves. Novel therapies inspired by these insights have begun to yield promising results in mouse models of these genetic diseases. Among these have been the use of small molecules or proteins to suppress gain-of-function mutations (eg, ascorbic acid for Charcot-Marie-Tooth disease type 1A) or to restore enzyme activities that are deficient because of loss-of-function mutations (eg, treatment of Fabry's disease with recombinant alpha-galactosidase or with low-molecular-weight alpha-galactosidase chaperones and treatment of spinal muscular atrophy with phenylbutyrate). Some of these therapies are already being tested in humans. Equally exciting is the prospect that small molecules and proteins will be identified that exert potent therapeutic effects in a broad spectrum of inherited and acquired motoneuron and peripheral nerve disorders.

Animals↗
PubMed1997

Disorders of puberty: inactivating and activating molecular mutations.

Recent developments have increased our understanding of the molecular mechanisms that are responsible for several disorders of puberty. Specific gene mutations have been identified in three syndromes, one that is associated with delayed puberty (Kallmann syndrome) and two that are associated with precocious puberty (McCune-Albright syndrome and familial male precocious puberty). Mutations in the KAL gene have been shown to be responsible for cases of X-linked Kallmann syndrome. This gene encodes a protein that is believed to be involved in neural target recognition and protease inhibition. In McCune-Albright syndrome, heterozygous, postzygotic somatic mutations of the alpha-subunit of the stimulatory guanine nucleotide binding protein Gs have been shown to stimulate constitutive G protein activation and long-term cyclic adenosine monophosphate production. Similarly, familial male precocious puberty has been linked to gain-in-function mutations that result in increased levels of cyclic adenosine monophosphate; however, these mutations are found in the luteinizing hormone receptor gene itself. The clinical manifestations and the recent molecular advances in each of these three syndromes are explored.

Cyclic AMP↗
PubMed2001

Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma.

Hepatoblastoma (HBL) is the most common malignant liver tumor in young children. Recent reports have shown that the beta-catenin gene was frequently mutated or deleted in HBLS: To elucidate the role of beta-catenin abnormalities in HBLs, we searched for mutations of beta-catenin and APC as well as expression of the target genes, cyclin D1, c-myc, and fibronectin, in 68 primary HBLS: The mutation analysis revealed that 44 (65%) tumors carried missense mutations or deletions of beta-catenin, all of which were somatic and targeted to the exon 3 encoding the amino acid residues involved in its degradation. However, no loss of function mutation of the APC gene was detected by the yeast functional assay. Of interest, beta-catenin mutation was significantly correlated with overexpression of the target genes, cyclin D1 and fibronectin, but not with that of c-myc in HBLs as measured by quantitative real-time reverse transcription-PCR. The immunohistochemical studies in 15 HBLs demonstrated that the nuclear/cytoplasmic accumulation of beta-catenin was positive in 13 tumors, 9 of which had the deletion or mutation of the gene. The significant correlation between the beta-catenin gene abnormality and the positive staining of cyclin D1 was also confirmed. Furthermore, the nuclear accumulation of beta-catenin was strongly associated with the poorly differentiated tumor cell components as well as with the positive staining of cyclin D1 within the tumor. Thus, our present results suggested that the gain of function mutation of beta-catenin played a crucial role in the malignant progression of HBL in vivo.

Adenomatous Polyposis Coli Protein↗
PubMed2005

Limited proteolysis differentially modulates the stability and subcellular localization of domains of RPGRIP1 that are distinctly affected by mutations in Leber's congenital amaurosis.

The retinitis pigmentosa GTPase regulator (RPGR) protein interacts with the retinitis pigmentosa GTPase regulator interacting protein-1 (RPGRIP1). Genetic lesions in the cognate genes lead to distinct and severe human retinal dystrophies. The biological role of these proteins in retinal function and pathogenesis of retinal diseases is elusive. Here, we present the first physiological assay of the role of RPGRIP1 and mutations therein. We found that the monoallelic and homozygous mutations, DeltaE1279 and D1114G, in the RPGR-interacting domain (RID) of RPGRIP1, enhance and abolish, respectively, its interaction in vivo with RPGR without affecting the stability of RID. In contrast to RID(WT) and RID(D1114G), chemical genetics shows that the interaction of RID(DeltaE1279) with RPGR is resistant to various stress treatments such as osmotic, pH and heat-shock stimuli. Hence, RID(D1114G) and RID(DeltaE1279) constitute loss- and gain-of-function mutations. Moreover, we find that the isoforms, bRPGRIP1 and bRPGRIP1b, undergo limited proteolysis constitutively in vivo in the cytoplasm compartment. This leads to the relocation and accumulation of a small and stable N-terminal domain of approximately 7 kDa to the nucleus, whereas the cytosolic C-terminal domain of RPGRIP1 is degraded and short-lived. The RID(D1114G) and RID(DeltaE1279) mutations exhibit strong cis-acting and antagonistic biological effects on the nuclear relocation, subcellular distribution and proteolytic cleavage of RPGRIP1 and/or domains thereof. These data support distinct and spatiotemporal subcellular-specific roles to RPGRIP1. A novel RPGRIP1-mediated nucleocytoplasmic crosstalk and transport pathway regulated by RID, and hence by RPGR, emerges with implications in the molecular pathogenesis of retinopathies, and a model to other diseases.

Animals↗
PubMed2000

Functional expression of the pore forming subunit of the ATP-sensitive potassium channel in Saccharomyces cerevisiae.

We have expressed the pore-forming subunits (Kir 6.1 and Kir 6.2) of the mammalian ATP-sensitive potassium channel in a potassium-transport deficient yeast strain (trk1 trk2). Functional expression of Kir 6.2 and Kir 6.1 can complement growth deficiency weakly and strongly respectively of the yeast strain on low-potassium medium. Mutations of Kir 6.2 that abolish ATP sensitivity (K185Q, I182Q) and enhance trafficking to the plasma membrane surface (Kir 6.2DeltaC36) lead to significantly better growth rescue. Growth rescue of Kir 6.1, Kir 6.2 and the above mutants can be inhibited by pharmacological agents (cesium ions, phentolamine and quinine) known to decrease channel activity by direct interaction with the pore forming subunit. Thus we have developed a system in yeast that can report both loss and gain of function mutations in these subunits and pharmacological interventions.

Adenosine Triphosphate↗
PubMed2006

The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.

PCSK9 is the ninth member of the proprotein convertase (PC) family. Some of its natural mutations have been genetically associated with the development of a dominant form of familial hyper- or hypocholesterolemia. The exact mechanism of action of PCSK9 is not clear, although it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. We analyzed the post-translational modifications of PCSK9 and show that it is sulfated within its prosegment at Tyr38. We also examined the susceptibility of PCSK9 to proteolytic cleavage by the other members of the PC family. The data show that the natural gain-of-function mutations R218S, F216L, and D374Y associated with hypercholesterolemia result in total or partial loss of furin/PC5/6A processing at the motif RFHR218 downward arrow. In contrast, the loss-of-function mutations A443T and C679X lead either to the lack of trans-Golgi network/recycling endosome localization and an enhanced susceptibility to furin cleavage (A443T) or to the inability of PCSK9 to exit the endoplasmic reticulum (C679X). Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. Thus, we propose that PCSK9 levels are finely regulated by the basic amino acid convertases furin and PC5/6A. The latter may reduce the lifetime of this proteinase and its ability to degrade the cell-surface LDL receptor, thereby regulating the levels of circulating LDL cholesterol.

Amino Acid Sequence↗