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PubMed1998

Genetics of apolipoprotein H (beta2-glycoprotein I) and anionic phospholipid binding.

Apolipoprotein H (apoH; also known as beta2-glycoprotein I), is an essential cofactor for the binding of certain antiphospholipid antibodies (APA) to anionic phospholipid. The gene coding for apoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect the binding of apoH to anionic phospholipids and consequently the production of APA. Our group has identified two common mutations at codons 306 (Cys-->Gly) and 316 (Trp-->Ser) in the fifth domain of apoH which affect the binding of apoH to anionic phospholipids (phosphatidylserine or cardiolipin). ApoH from serum samples homozygous for each of these mutations or compound heterozygotes for both mutations showed no binding with anionic phospholipids on ELISA. In vitro mutagenesis and transient expression of these mutations in COS-1 cells followed by cardiolipin binding studies confirmed that Gly306 and Ser316 are causative mutations. Our data indicate that the fifth domain of apoH is essential for anionic phospholipid binding and genetically determined variation in this domain can affect the production of apoH-dependent APA.

Alleles↗
PubMed2006

Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription.

BACKGROUND: Transcription of HIV-1 genes is activated by HIV-1 Tat protein, which induces phosphorylation of RNA polymerase II (RNAPII) C-terminal domain (CTD) by CDK9/cyclin T1. Earlier we showed that CDK2/cyclin E phosphorylates HIV-1 Tat in vitro. We also showed that CDK2 induces HIV-1 transcription in vitro and that inhibition of CDK2 expression by RNA interference inhibits HIV-1 transcription and viral replication in cultured cells. In the present study, we analyzed whether Tat is phosphorylated in cultured cells by CDK2 and whether Tat phosphorylation has a regulatory effect on HIV-1 transcription. RESULTS: We analyzed HIV-1 Tat phosphorylation by CDK2 in vitro and identified Ser16 and Ser46 residues of Tat as potential phosphorylation sites. Tat was phosphorylated in HeLa cells infected with Tat-expressing adenovirus and metabolically labeled with 32P. CDK2-specific siRNA reduced the amount and the activity of cellular CDK2 and significantly decreased phosphorylation of Tat. Tat co-migrated with CDK2 on glycerol gradient and co-immunoprecipitated with CDK2 from the cellular extracts. Tat was phosphorylated on serine residues in vivo, and mutations of Ser16 and Ser46 residues of Tat reduced Tat phosphorylation in vivo. Mutation of Ser16 and Ser46 residues of Tat reduced HIV-1 transcription in transiently transfected cells. The mutations of Tat also inhibited HIV-1 viral replication and Tat phosphorylation in the context of the integrated HIV-1 provirus. Analysis of physiological importance of the S16QP(K/R)19 and S46YGR49 sequences of Tat showed that Ser16 and Ser46 and R49 residues are highly conserved whereas mutation of the (K/R)19 residue correlated with non-progression of HIV-1 disease. CONCLUSION: Our results indicate for the first time that Tat is phosphorylated in vivo; Tat phosphorylation is likely to be mediated by CDK2; and phosphorylation of Tat is important for HIV-1 transcription.

Cyclin-Dependent Kinase 2↗
PubMed1990

Functional elements of the steroid hormone-responsive promoter of mouse mammary tumor virus.

Transcription from the promoter of mouse mammary tumor virus is subject to induction by several classes of steroid hormones as well as to repression by a negative regulatory element present in the long terminal repeats of proviral DNA. In order to characterize the functional elements of the promoter that in some way must respond to these regulatory signals, a number of promoter mutations were constructed, including a set of linker-scanning mutations across the entire promoter region. Analysis of these mutated promoters with a transient-transfection assay defined at least three mutation-sensitive promoter elements that are required for both basal and hormone-induced transcription. One mutation-sensitive region contains a TATA element located at approximately position -30 with respect to the start of transcription. A second mutation-sensitive region contains two 10-base-pair direct repeats located between positions -60 and -38, within which are embedded three copies of octamer-related sequences; complete disruption of this region of the promoter leads to a more severe decrease in transcription than do any of the linker-scanning mutations, suggesting that the repeated sequences may be at least partially functionally redundant. Gel electrophoresis mobility shift assays were used to demonstrate specific binding of a nuclear protein to this region of the promoter. A third mutation-sensitive region contains a binding site for nuclear factor 1 (NF-1) located between positions -77 and -63. Site-directed mutations in the NF-1-binding site which increase the apparent affinity of NF-1 for the promoter in vitro do not decrease the hormone dependence of transcription, suggesting that transcriptional activation mediated by steroid hormone-receptor complexes cannot be explained by facilitation or stabilization of the interaction of promoter sequences with NF-1 and consistent with the idea that binding of NF-1 is not rate determining in transcription from the mouse mammary tumor virus promoter. None of the promoter mutations functionally separates basal from glucocorticoid-induced transcription, suggesting that hormone induction does not make the promoter independent of any of the DNA-binding factors required for its basal activity.

Animals↗
PubMed1994

Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid.

It has recently been shown that somatic and germ line mutations of the TSH receptor gene cause autonomous hyperfunctioning thyroid adenomas and nonautoimmune toxic thyroid hyperplasia by constitutive activation of the TSH receptor. A "saturated" map of these mutations is a prerequisite for a systematic screening for these clinically important mutations. In this context, it is also of interest to determine whether different amino acid substitutions at the same residue cause constitutive activation of the TSH receptor, as suggested by site-directed mutagenesis of the alpha 1 beta-adrenergic receptor. We, therefore, screened further hyperfunctioning autonomous adenomas of the thyroid for constitutively activating mutations. We identified two new somatic mutations, changing alanine in position 623 to valine (A623V) and threonine in position 632 to isoleucine (T632I). Both mutations constitutively activated cAMP when transiently expressed in COS cells. Together with neighboring mutations, the T632I mutation demonstrates the importance of transmembrane domain VI for the activation of the TSH receptor and characterizes it as a hot spot for constitutively activating mutations. The previously identified A623I and the newly identified A623V mutations demonstrate that several amino acid substitutions at the same residue can cause constitutive activation of the TSH receptor.

Adenoma↗
PubMed1994

Haemophilia B Leyden: the effect of mutations at position +13 on the liver-specific transcription of the factor IX gene.

Haemophilia B Leyden is characterized by low plasma levels (< or = 1-13% of normal) of blood coagulation factor IX during childhood. After the onset of puberty, plasma factor IX levels gradually rise, probably under the influence of androgens. Single point mutations have been detected in the factor IX promoter at -21, -20, -6, -5, +6, +8 and +13. This paper examines how two of these mutations (a deletion of an A, and an A-->G substitution at +13) interfere with normal factor IX gene transcription. It is shown that both mutations do impair factor IX promoter activity in transiently transfected HepG2 cells. The mutations at +13 lie in a region (+1 to +18) that is considered to contain a binding site for the CCAAT/enhancer binding protein. Transactivation by the CCAAT/enhancer binding protein alpha of the wild-type and mutated factor IX promoter (-192 to +38) resulted in an approximately four-fold and approximately two-fold, respectively, increase of CAT activity. Gel mobility shift assays revealed that the binding of the CCAAT/enhancer binding protein alpha is disrupted by both the deletion of an A, and the A-->G substitution at +13. The role of two additional bZIP factors, D-site binding protein and liver-enriched transcriptional activator protein, in the binding and activation of the +13 factor IX promoter region was examined. The D-site binding protein binds to the factor IX promoter region (+1 to +18) in gel mobility shift assays. The deletion of an A at +13 does not interfere with the binding of the D-site binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1991

Functional analysis of the trans-acting factor binding sites of the mouse alpha-fetoprotein proximal promoter by site-directed mutagenesis.

The trans-acting factors of the mouse alpha-fetoprotein proximal promoter (-202 base pairs) are aligned as follows: regions Ia (HNF-1), Ib (C/EBP), II (NF-1 or C/EBP), II' (NF-1 or HNF-1), III (NP-III), IV (NP-IV), Va (NP-Va), and Vb (C/EBP). Site-specific mutation abolished protein binding to the corresponding mutated site with the exception of the NF-1 site, in which mutation causes partial protection. Transient expression analyses indicate that chloramphenicol acetyl-transferase (CAT) activity is reduced by mutations in regions Ia, II', Ib, II, and IV. Mutation of region III causes an increased activity and mutation of regions Va and Vb shows a slight inhibitory effect. Linking alpha-fetoprotein enhancer I to the wild type promoter resulted in a 12-fold stimulation of CAT activity. The activity of promoters with mutated C/EBP-binding sites (Ib, II, and Vb), was slightly above controls, indicating that enhancer I can reverse the effect of these mutations. Inhibition or stimulation of promoter activity resulting from mutations of the HNF-1 or NP-III binding sites, respectively, persisted when enhancer I was linked to the promoters, indicating that enhancer I cannot rescue these mutations. Mutation of both HNF-1-binding sites resulted in greater than 90% inhibition of CAT expression with and without enhancer I, indicating these sites are essential for promoter activity. The stimulation of promoter activity by mutation of the NP-III site suggests that this site may be essential for repression or attenuation of the alpha-fetoprotein gene. Our studies indicate that regulation of the alpha-fetoprotein gene requires the combinatorial effect of multiple cis- and trans-acting elements in the proximal promoter and that enhancer I may provide a factor(s) that specifically rescue the promoter from the inhibitory effect of mutation in the C/EBP-binding sites.

Animals↗
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↗
PubMed1996

Positive and negative regulatory elements in the murine p53 promoter.

In order to understand the basis for regulated as well as de-regulated expression of the p53 tumor suppressor gene, we have focused on characterizing the transcriptional regulation of the p53 gene. Here we present evidence for the existence of two additional upstream regulatory elements in the murine p53 promoter. One of these sites maps to a region between -296 to -270 and the second one between -255 to -226 relative to the major transcription initiation site. These two sites are referred to as binding sites for PBF I and II, respectively. Nucleotide bases that have been found to be critical for the binding of nuclear factors to these sites are 5'-AGA-3' (-282 to -280) in binding site I and 5'-ACAG-3' (-246 to -243) in binding site II. Mutational analyses in conjunction with transient transfection assays indicated that the factor that binds to the region between -245 to -242 (PBF II) plays a positive regulatory role p53 promoter activity. This was demonstrated by the observation that promoter mutations that abolished binding to this site, showed a decreased level of activity as compared to the wild type promoter. In analogous experiments, mutational anlayses and transient transfection assays indicated that the factor that binds to the region between -282 to -280 (PBF I) plays a negative regulatory role in p53 promoter activity. This was demonstrated by the observation that promoter mutations that abolished binding to this site, showed an increased level of activity as compared to the wild type promoter.

3T3 Cells↗
PubMed1988

Light reduces the excitation efficiency in the nss mutant of the sheep blowfly Lucilia.

The nss (no steady state) phototransduction mutant of the sheep blowfly Lucilia was studied electrophysiologically using intracellular recordings. The effects of the nss mutation on the receptor potential are manifested in the following features of the light response. (a) The responses to a flash or to dim lights are close to normal, but the receptor potential decays close to the baseline level during prolonged illumination after a critical level of light intensity is reached. (b) The decline of the response is accompanied by a large reduction in responsiveness to light that recovers within 20 s in the dark. (c) The full reduction in responsiveness to light is reached when approximately 13% of the photopigment molecules are converted from rhodopsin (R) to metarhodopsin (M). (d) A maximal net pigment conversion from R to M by blue light induces persistent inactivation in the dark, without an apparent voltage response. This inactivation could be abolished at any time by M-to-R conversion with orange light. The above features of the mutant indicate that the effect of the nss mutation on the light response of Lucilia is very similar to the effects of the transient receptor potential (trp) mutation on the photoreceptor potential of Drosophila. Noise analysis and voltage measurements indicate that the decay of the receptor potential is due to a severe reduction in the rate of occurrence of the elementary voltage responses (bumps). The bumps are only slightly modified in shape and amplitude during the decline of the response to light of medium intensity. There is also a large increase in response latency during intense background illumination. These results are consistent with the hypothesis that separate, independent mechanisms determine bump triggering and bump shape and amplitude. The nss mutation affects the triggering mechanism of the bump.

Animals↗
PubMed1997

Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism.

Constitutively activating germline mutations in the TSH receptor (TSHR) gene have been identified as a cause of autosomal dominant nonautoimmune hyperthyroidism and sporadic congenital hyperthyroidism. We report a 10-yr-old boy and his 31-yr-old mother, both presenting with a history of recurring toxic thyroid hyperplasia and no evidence for autoimmune thyroid disease. In the boy, onset of hyperthyroidism and goiter was neonatal. In the mother, onset of thyroid disease dates back to early childhood. There was no history of thyroid disease in the rest of the family. Screening for germline mutations in exon 10 of the TSHR was performed by direct sequencing of genomic DNA extracted from peripheral blood leukocytes of both patients. In the boy and his mother, an identical heterozygous TSHR mutation was identified, exchanging leucine for phenylalanine at residue 629 of the TSHR (TTG-->TTT). Transient expression of the mutated TSHR construct in COS-7 cells confirmed the constitutive activity of the new TSHR germline mutation. This is the second family displaying congenital manifestation of hyperthyroidism in familial nonautoimmune hyperthyroidism.

Adult↗
PubMed1994

A mutant renin gene in familial elevation of prorenin.

A case of familial elevation of plasma prorenin levels was discovered during an epidemiological survey of a Dutch population. Trypsin-activated prorenin was elevated in the 58-year-old father, his son, and one of his sisters. All family members were normotensive and had normal plasma renin activities. Exon sequencing of the renin gene of the proband and of his son after polymerase chain reaction amplification identified a point mutation in the last exon of the gene (exon 10). A cytosine to thymine transition creates a premature stop codon at position 387 resulting in a truncated form of renin with 20 amino acids deleted from the carboxyl terminus. All family members presenting high levels of plasma prorenin were heterozygous for the mutation. Expression vectors carrying normal or mutated renin cDNA were transiently transfected into AtT-20 cells to test in vitro the functional consequences of this mutation. Measurements of renin activity and pulse-chase experiments indicated that the truncated renin is inactive and not secreted from transfected cells. We hypothesize that the abnormal gene product of the mutated allele alters renin sorting and propose that plasma prorenin elevation may result from a compensatory mechanism.

Animals↗
PubMed2006

New strategy for comprehensive analysis of gene functions in embryonic stem cells.

At present, the limitation of Phenotype-based genetic screening in embryonic stem cells (ESCs) is the diploid nature of the genome. Since it is known that cells deficient in the Bloom's syndrome gene (Blm) show an increased rate of homologous recombination, we have developed a new system to conditionally regulate the Blm allele for introduction of bi-allelic mutations across the genome. Transient deficiency of Blm induces homologous recombination not only between sister chromatids but also between homologous chromosomes, resulting in a high rate of loss of heterozygosity (LOH). Introduction of genome-wide mutations in ESCs can be achieved by retroviral vector. In combination, using genome-wide mutagenesis and transient loss of Blm expression, we have generated ES libraries with bi-allelic mutations. These results show that this new system is very efficient for identifying gene functions in ESCs.

Alleles↗
PubMed1999

Molecular analysis of methylmalonyl-CoA mutase deficiency: identification of three missense mutations in mut0 patients.

Genetic defects in the methylmalonyl-CoA mutase (MCM) gene cause methylmalonic acidemia (MMA). Only three mutations have been reported among Oriental patients to date. We studied fibroblast cell lines established from three Japanese patients with MCM deficiency. Enzymatic study showed that these patients had the muttype of MMA. Nucleotide sequencing of MCM cDNAs identified three missense mutations: a T to A change at nucleotide position 2082, which results in an amino acid substitution of Glu669 for valine (V669E); a T to A change at position 1179 with the corresponding amino acid substitution of Asp368 for valine (V368D); and a G to A change at position 1182 with the corresponding amino acid substitution of His369 for arginine (R369H). Each of the three missense mutations abolished MCM activity according to a transient expression study. Alignment of these mutations with a recently reported homology model of human MCM allowed us to speculate on the effect of these nonconservative amino acid substitutions on MCM activity: V368D and R369H affected residues in the beta/alpha-(TIM-) barrel domain, on one of the two alpha-helices that form the dimer interface, while V669E altered a residue in the adenosylcobalamin-binding domain in the C terminus.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

A mutation in the GABAA receptor alpha 1 subunit linked to human epilepsy affects channel gating properties.

A genetic component is associated with the development of many forms of epilepsy. Recently, mutations in the GABAA receptor have been linked to several inherited epilepsies. One of these mutations is a non-conservative change of alanine to aspartate in the third transmembrane domain of the alpha1 subunit. To determine the functional consequences of this alteration, mutated alpha subunits were transiently transfected along with wild-type beta3 and gamma2L subunits into HEK-293T cells. The mutated alpha1(A294D) subunit reduced GABA sensitivity of the receptor, increased the deactivation rate and slowed desensitization. The mutation caused a reduction in channel open time but no change in single channel conductance. Studies with additional mutants, altering the charge and/or size of the side-chain, indicated that both size and hydrophobicity of the residue at this location influence channel gating. The effects on GABA sensitivity, deactivation rate and channel open time are consistent with a reduced efficacy of channel gating, and would be expected to decrease GABAergic neurotransmission. The alpha1 subtype is the most widely expressed of the alpha subunits, with expression increasing throughout development. Therefore, production of the mutated subunit could cause global hyperexcitability throughout the brain, leading to generalized seizures with juvenile onset.

Amino Acid Sequence↗
PubMed1996

Ser72Pro active-site disease mutation in human lysosomal aspartylglucosaminidase: abnormal intracellular processing and evidence for extracellular activation.

Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by deficient activity of aspartylglucosaminidase (AGA). We report here a T214C mutation leading to a Ser72Pro substitution in four Arab families. This is the first naturally occurring AGU mutation involving an active-site amino acid of this recently crystallized hydrolase and it seems to represent the second most common AGU mutation worldwide. The intracellular consequences of the Ser72Pro mutation were analyzed by transient expression in COS-1 cells and we were able to demonstrate that this active-site mutation most probably does not destroy the enzyme activity per se, but specifically prevents the proteolytic activation cleavage of AGA in the endoplasmic reticulum (ER). The mutant enzyme is, however, folded correctly enough to allow mannose-6-phosphorylation and targeting to lysosomes. The overexpressed mutant enzyme remained inactive intracellularly, but the secreted mutant precursor was proteolytically activated extracellularly, resulting in a similar subunit composition to that in the wild-type AGA in the ER. The partially activated mutant enzyme was endocytosed further by the recipient cells. These data demonstrate that the proteolytic activation of AGA can also occur extracellularly and suggest that the driving mechanism of AGA precursor cleavage is autocatalytic.

Animals↗
PubMed1998

A point mutation within exon 5 of the WT1 gene of a sporadic unilateral Wilms' tumor alters gene function.

The Wilms' tumor suppressor gene, wt1, encodes a zinc-finger transcription factor, WT1, that represses transcription of a number of growth-promoting genes and inhibits cell growth. The transcripts of wt1 undergo two alternative splicing events, giving rise to four isoforms of mRNA in constant ratios. The first alternative splice introduces an extra exon 5, which encodes 17 amino acid residues inserted between the transcription regulatory domain and the DNA binding domain of WT1. Previously, we demonstrated that the 17-amino acid domain functioned as a transcription repressor when it was fused with the DNA binding domain of WT1. We have now identified a point mutation within exon 5 of wt1 in a sporadic unilateral Wilms' tumor patient. The mutation changes the last of the 17 amino acids from asparagine to serine. The protein isoform of WT1 carrying this mutation exhibited a 2-3-fold lower transcription-repressing activity than wild-type WT1 in transient cotransfection assays. The mutation also decreased growth-inhibiting activity of WT1 in two osteosarcoma cell lines, U2OS and Saos-2. By diminishing transcription-repressing and growth-inhibiting activities of WT1, this naturally occurring mutation within exon 5 of wt1 may disturb the normal function of the protein and lead to the uncontrolled cell growth characteristic of Wilms' tumor.

Alternative Splicing↗
PubMed1999

Identification and characterization of the molecular lesion causing mucopolysaccharidosis type I in cats.

Mucopolysaccharidosis Type I (MPS I) is the lysosomal storage disease caused by the deficient activity of alpha-L-iduronidase (IDUA). In man, MPS I can occur in severe, mild, or intermediate forms known as the Hurler, Scheie, or Hurler/Scheie syndromes, respectively. MPS I also has been described in cats, dogs, and mice. This manuscript reports the identification and characterization of the mutation causing MPS I in cats. To obtain wild-type feline IDUA cDNAs, two PCR-based strategies were used. PCR primers were constructed from a conserved region of the published human and dog sequences and used to amplify a 224-bp IDUA fragment from normal cat genomic DNA. This fragment was then used to screen a feline uterus cDNA library. PCR also was used to directly amplify IDUA fragments from the same cDNA library. Two overlapping feline IDUA cDNAs encoding 466 amino acid residues of the feline IDUA polypeptide ( approximately 85% of the mature protein based on comparison to the human, dog, and mouse sequences) were obtained by these strategies. To identify the mutation causing MPS I in cats, DNA sequencing was carried out on the corresponding IDUA region from several affected animals. A 3-bp deletion was found on both IDUA alleles in each of the MPS I animals, predicting the deletion of a single aspartate residue from the feline IDUA polypeptide. To confirm the authenticity of this mutation, heteroduplex, SSCP, and transient expression studies were carried out. Over 100 animals from the MPS I colony were screened for the presence of the mutation by heteroduplex and SSCP analyses-in all cases the presence of the 3-bp deletion was 100% concordant with the disease phenotype. For transient expression studies, the two partial, overlapping feline cDNAs were combined and joined in-frame to the 5' end of the canine IDUA cDNA. This wild-type, hybrid cDNA expressed IDUA activity up to sixfold over endogenous levels after transfection into COS-1 cells. A modified full-length IDUA cDNA containing the 3-bp deletion did not express IDUA activity in a transient expression system, providing proof that this lesion was the cause of feline MPS I.

Animals↗
PubMed2002

Familial transient erythroblastopenia of childhood is associated with the chromosome 19q13.2 region but not caused by mutations in coding sequences of the ribosomal protein S19 (RPS19) gene.

Transient erythroblastopenia of childhood (TEC) is a rare condition, which at onset may be difficult to distinguish from Diamond-Blackfan anaemia (DBA). We have previously shown that mutations in the ribosomal protein S19 gene (RPS19) cause DBA. In order to clarify whether TEC and DBA are allelic, we investigated the segregation of markers spanning the RPS19 gene region on chromosome 19q13.2 and performed sequence analysis of all exons in the RPS19 gene in seven TEC sibling pairs. Linkage analysis supported allelism for TEC and DBA at the RPS19 gene locus and implies molecular mechanisms other than structural mutations in the RPS19 gene.

Adult↗