An atypical case of hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome)

Complete HG-PRT deficiency was established by means of direct enzyme assay and autoradiography in a patient with relatively little, if any, of the neurological and psychomotor symptoms of the Lesch-Nyhan syndromes. Family study revealed two other HG-PRT negative males. Hair root analysis was used for carrier detection. Linkage study produced no evidence of close linkage between Xga and HG-PRT loci.     

An atypical case of hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome)

This paper describes an adult patient, with gout and without any demonstrable activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HG-PRT). Few of the neurological abnormalities generally associated with severe HG-PRT deficiency were exhibited by this patient. Psychological studies, however, disclosed that some characteristics of the behaviour anomaly in the Lesch-Nyhan syndrome are present, but only in a concealed form.     

Use of phytohaemagglutinin stimulated lymphocytes to study effects of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency on polynucleotide and protein synthesis in the Lesch-Nyhan syndrome.

The incorporation of [14C]thymidine and [14C]uridine into the nucleoprotein, and [14C]phenylalanine into the protein by phytohaemagglutinin (PHA) stimulated lymphocytes from a patient with the Lesch-Nyhan syndrome [hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8 HGPRT) deficiency] and controls, was studied over 72 hours of incubation, with and without azaserine to block de novo purine biosynthesis. No difference was observed between the values obtained for Lesch-Nyhan and control lymphocytes, when PHA-stimulated without added azaserine. The percentage reduction in the incorporation of precursors into nucleoprotein and protein after PHA stimulation in the presence of azaserine was more obvious in the lymphocytes of the patient with the Lesch-Nyhan syndrome than in the controls after the shorter incubation periods at the lower rates of synthesis. Blocking the de novo purine biosynthetic pathway, in control PHA stimulated lymphocytes, inhibited transformation, whereas loss of the purine salvage enzyme HGPRT did not have this effect. These results are compatible with the view that the brain and bone-marrow damage that occur in the Lesch-Nyhan syndrome are the result of lack of HGPRT in tissues with little de novo purine biosynthetic capability. Other tissues with both pruine biosynthetic and salvage pathways are less vulnerable to the enzyme defect. Some possible mechanisms by which HGPRT deficiency could act are discussed. We suggest that inability to increase the supply of guanylic acid (GMP) in response to a mitotic stimulus may mediate the effect of HGPRT deficiency.     

A novel point mutation in the mitochondrial tRNA(Trp) gene produces a neurogastrointestinal syndrome

We report a novel, heteroplasmic point mutation in the mitochondrial tRNA for tryptophan at position 5532. The mutation was present in all the tissues studied and segregated with the biochemical defect, with higher levels of mutation present in cytochrome c oxidase-deficient muscle fibres. The patient manifested a neurogastrointestinal syndrome with features including failure to thrive, psychomotor retardation, ophthalmoplegia, sensorineural deafness and encephalopathy together with vomiting, diarrhoea and colitis.     

A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome

Homozygosity mapping and linkage analysis in a Turkish family with autosomal recessive prelingual sensorineural hearing loss revealed a 15-cM critical region at 17q25.1–25.3 flanked by the polymorphic markers D17S1807 and D17S1806. The maximum two-point lod score was 4.07 at =0.0 for the marker D17S801. The linkage interval contains the Usher syndrome 1G gene (USH1G) that is mutated in patients with Usher syndrome (USH) type 1g and encodes the SANS protein. Mutation analysis of USH1G led to the identification of a homozygous missense mutation D458V at the –3 position of the PDZ binding motif of SANS. This mutation was also present homozygously in one out of 64 additional families from Turkey with autosomal recessive nonsyndromic hearing loss and heterozygously in one out of 498 control chromosomes. By molecular modeling, we provide evidence that this mutation impairs the interaction of SANS with harmonin. Ophthalmologic examination and vestibular evaluation of patients from both families revealed mild retinitis pigmentosa and normal vestibular function. These results suggest that these patients suffer from atypical USH.E. Kalay and A.P.M. de Brouwer contributed equally to this work     

Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient

Lesch-Nyhan (LN) disease is a severe X-linked recessive neurological disorder associated with a loss of hypoxanthine guanine phosphoribosyltransferase activity (HPRT, EC 2.4.2.8). We have studied the second example of a female patient with LN disease. The molecular basis of HPRT deficiency in this patient was a previously undescribed nucleotide substitution in exon 6. In this gene, designated HPRT PARIS, a single nucleotide substitution from T to G at base position 558 changed a tyrosine (TAT) to a codon STOP (TAG) (Y153X). Analysis of the mother revealed a normal sequence of the HPRT cDNA and demonstrated that this mutation arose through a de novo gametic event. Allele-specific amplification of exon 6 from the patient's genomic DNA confirmed the single base substitution and showed that the patient was heterozygous for this mutation. Investigation of X-chromosomal inactivation by comparison of methylation patterns of patient's DNA isolated from fibroblasts, T lymphocytes, and polymorphonuclear cells digested with PstI and BstXI, with or without HpaII, and hybridized with M27 β probe indicated a nonrandom pattern of X-chromosomal inactivation in which there was preferential inactivation of the maternal allele. The data indicate that nonrandom X-inactivation leading to selective inactivation of the maternal gene and a de novo point mutation in the paternal gene were responsible for the lack of HPRT activity in this patient. © 1996 Wiley-Liss, Inc.     

Molecular genetic study of a Japanese family with Lesch-Nyhan syndrome: A point mutation at the consensus region of RNA splicing (HPRTKEIO)

Summary Complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) causes Lesch-Nyhan syndrome. A single nucleotide substitution of G to T at the 3-end of intron 3 in the splicing consensus region has been identified in one allele of the HPRT gene from a mother predicted to be a heterozygous Lesch-Nyhan carrier. Utilizing aBfaI restriction site which was lost in the mutation as an indicator, family study showed that the mother and her only daughter were heterozygotes but the mother's sister did not have the mutant allele. The mutation generated splicing error and resulted in two types of abnormal mRNA. The major altered mRNA, named Type I, skipped the exon 4 and is predicted to produce a protein deleted of 22 amino acid residues. The other, Type II, having a 9-bp deletion at the 5-end of exon 4, can result in a protein lacking 3 amino acids, from codon 107 to 109.     

A novelde novo mutation in HPRT gene responsible for Lesch-Nyhan syndrome (HPRTosaka)

Summary A virtually complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) causes Lesch-Nyhan syndrome. A novel mutation of HPRT gene in a Japanese Lesch-Nyhan family has been identified using mRNA and genomic DNA from peripheral blood cells. A single nucleotide substitution of T to C in exon 3 resulted in a mis-sensemutation, CTC (Leu) to CCC (Pro), at codon 65. Utilizing anMnlI restriction site which was lost in the mutation as an indicator,a family study showed that the mother was normal not having the mutant gene. The mutation was ade novo event that had occurred in the germ cells of the mother or in the proband during the early phase of fetal development.     

Molecular analysis of hypoxanthine guanine phosphoribosyltransferase (HPRT) gene in five Korean families with Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome is caused by the complete deficiency of hypoxanthine guanine phosphoribosyl-transferase (HPRT). By the analysis of genomic DNA and mRNA using the polymerase chain reaction (PCR) technique coupled with direct sequencing, five independent mutations in HPRT genes have been identified in Korean Lesch-Nyhan families. Two novel mutations and three previously reported mutations have been found in five independent families. Heterozygous carriers were detected in all the families, and prenatal diagnosis was carried out in two families.     

A novel point mutation (R840S) in the androgen receptor in a Brazilian family with partial androgen insensitivity syndrome

Mutations of the androgen receptor gene causing androgen insensitivity syndrome in 46, XY individuals, result in phenotypes ranging from complete female to ambiguous genitalia to males with minor degrees of undervirilization. We studied two Brazilian brothers with partial androgen insensitivity syndrome. They were born with perineal hypospadias, bifid scrotum, small penis and cryptorchidism, and developed gynecomastia at puberty. Genomic DNA was extracted and denaturinggradient gel electrophoresis of exon 7 of the androgen receptor gene followed by sequence analysis revealed a new mutation, a C A transversion, altering codon 840 from arginine (CGT) to serine (AGT). R840 is located in the androgen binding domain, in a “hot spot” region, important for the formation and function of the hormone receptor‐complex and within the region that is involved in androgen receptor dimerization. Replacement of arginine (basic) by serine (neutral and polar) is a nonconservative substitution. Three mutations in this residue (R840C, R840G nonconservative and R840H, conservative) were previously reported in patients with partial androgen insensitivity syndrome and when expressed “in vitro” lead to a subnormal transactivation of a reporter gene. We conclude that the novel R840 mutation in the androgen receptor is the cause of partial androgen insensitivity syndrome in this Brazilian family. Hum Mutat 14:353, 1999. © 1999 Wiley‐Liss, Inc.     

A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype

Mutations in the human minK gene KCNE1 have been linked to autosomal dominant and autosomal recessive long-QT (LQT) syndrome, a cardiac condition predisposing to ventricular arrhythmias. minK and KvLQT1, the LQT1 gene product, form a native cardiac K+ channel that regulates the slowly delayed rectifier potassium current I(Ks). We used single-strand conformation polymorphism and sequencing techniques to identify novel KCNE1 mutations in patients with a congenital LQT syndrome of unknown genetic origin. In 150 unrelated index patients a missense mutation (V109I) was identified that significantly reduced the wild-type I(Ks) current amplitude (by 36%) when coexpressed with KvLQT1 in Xenopus oocytes. Other biophysical properties of the I(Ks) channel were not altered. Since we observed incomplete penetrance (only one of two mutation carriers could be diagnosed by clinical criteria), and the family's history was unremarkable for sudden cardiac death, the 109I allele most likely causes a mild phenotype. This finding may have implications for the occurrence of "acquired" conditions for ventricular arrhythmias and thereby the potential cardiac risk for asymptomatic mutation carriers still remains to be determined.     

Identification of a novel point mutation (S65T) in α-galactosidase A gene in Chinese patients with Fabry disease

Fabry disease is an X-linked inborn error of sphingolipid catabolism resulting from deficient enzyme activity of α-galactosidase A. The molecular defects of human α-galactosidase A gene causing Fabry disease have been characterized, including gene rearrangement and point mutations, which show the genetic heterogeneity in Fabry disease. To characterize the molecular defects of these patients, each exon of α-galactosidase A gene including intron-exon junctions were PCR amplified using biotin-labelled primer and sequenced using magnetic beads solid-phase sequencing. A G to C transversion was identified in the last nucleotide of exon 1 in two unrelated Chinese patients. This mutation obliterates an EcoN1 restriction site. Family studies show close linkage with the affected family members. Screening of 100 alleles (22 males, 39 females) of unrelated normal Chinese can not find this mutation. This mutation not only changes the amino acid from serine to threonine, but also likely cause splicing defects. To our knowledge, this is the first report of mutation in Chinese patients with Fabry disease, and a novel mutation causing Fabry disease not reported in literature previously. Hum Mutat 11:328–330, 1998. © 1998 Wiley-Liss, Inc.     

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS‐MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 –a condition known as neurofibromatosis–Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP‐domain. Additional RAS‐MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP‐domain of NF1 should be prioritized in NFNS.     

Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G)

Mutation of mitochondria) (mt) DNA at nucleotide (nt) 8993 has been reported to cause neurogenic weakness, ataxia, retinitis pigmentosa (NARP), or Leigh syndrome (LS). We report a family in whom the mutation was expressed clinically as LS and hypertrophic cardiomyopathy (CMP) in a boy who presented with a history of developmental delay and hypotonia, and who had recurrent lactic acidosis. The mother's first pregnancy resulted in the birth of a stillborn female; an apparently healthy older brother had died suddenly (SIDS) at age 2 months. MtDNA analysis identified the presence of the T8993G point mutation, which was found to be heteroplasmic in the patient's skeletal muscle (90%) and fibroblasts (90%). The identical mutation was present in leukocytes (38%) isolated from the mother, but not from the father or maternal grandmother. Our findings expand the clinical phenotype of the nt 8993 mtDNA mutation to include hypertrophic cardiomyopathy and confirm its cause of LS. © 1994 Wiley-Liss, Inc.     

A novel SLC12A1 mutation in Bedouin kindred with antenatal Bartter syndrome type I

Four affected individuals of consanguineous kindred presented at infancy with an apparently autosomal recessive syndrome of polyuria and hypokalemic metabolic alkalosis, following maternal polyhydramnios and premature delivery, culminating in severe failure to thrive. Hypercalciuria, nephrocalcinosis, and hyperaldosteronism were further apparent as well as an unusual finding of intermittent hypernatremia. Additionally, all patients demonstrated variable micrognathia with upper respiratory airway abnormalities. As neither postnatal hyperkalemia nor permanent hearing deficits were shown, clinical assessment was consistent with antenatal Bartter syndrome (ABS) type I, which was never described before in the Israeli Bedouin population. Through genome‐wide linkage analysis, we identified a single ～3.3 Mbp disease‐associated locus on chromosome 15q21.1, segregating within the pedigree. Whole‐exome sequencing revealed a single novel homozygous missense mutation within this locus, in SLC12A1, encoding the Na‐K‐Cl cotransporter, NKCC2, in accordance with the clinical diagnosis. In this concise study, we report a novel missense mutation within the SLC12A1 gene, causing a severe form of ABS type I, the first to be described in Israeli Bedouins, with unusual clinical features of hypernatremia caused by nephrogenic diabetes insipidus and putatively related micrognathia with upper airway abnormalities .     

A novel mutation in the G4.5 (TAZ) gene in a kindred with Barth syndrome

Barth syndrome is an X-linked recessive disorder characterised by dilated cardiomyopathy and a variable expression of skeletal myopathy, short statue and neutropenia. Molecular genetic analysis is currently the most reliable diagnostic method. A kindred with a novel 535delC mutation in the G4.5 (TAZ) gene responsible for Barth syndrome is presented. Beside the patient, the same mutation was detected in patient's mother and grandmother. In contrast to the so far reported patients with mutations in the same region of G4.5 (TAZ) gene, the patient described here has only a mild and transitory clinical presentation. This could be attributed to alternative splicing of G4.5 (TAZ) gene, since mRNA lacking exon 6 (with 535delC mutation) was detected. Genetic analysis of the G4.5 (TAZ) gene was helpful for establishing the precise diagnosis of Barth syndrome and for adequate genetic counselling. Predicting the phenotype on the basis of mutations is unreliable especially if mutations are localised in alternatively spliced exons of the G4.5 (TAZ) gene which may result in a milder clinical presentation than expected.