The ABCR gene in recessive and dominant Stargardt diseases: a genetic pathway in macular degeneration.

Stargardt disease (STGD) is a juvenile-onset macular dystrophy and can be inherited in an autosomal recessive or in an autosomal dominant manner. Genes involved in dominant STDG have been mapped to human chromosomes 13q (STGD2) and 6q (STGD3). Here, we identify a new kindred with dominant STGD and demonstrate genetic linkage to the STGD3 locus. Because of a more severe macular degeneration phenotype of one of the patients in this family, the gene responsible for the recessive STGD1, ABCR, was analyzed for sequence variants in all family members. One allele of the ABCR gene was shown to carry a stop codon-generating mutation (R152X) in three family members, including the one patient who had inherited also the dominant gene. A grandparent of that patient with the same ABCR mutation developed age-related macular degeneration (AMD), consistent with our earlier observation that some variants in the ABCR gene may increase susceptibility to AMD in the heterozygous state. Based on these results, we propose that there is a common genetic pathway in macular degeneration that includes genes for both recessive and dominant STGD.     

Spectrum of the GJB2 mutations in Belarussian patients with hearing loss. Findings of pilot genetic screening of hearing impairment in newborns

A total of 111 unrelated probands and their 8 sibs from Grodno oblast (Belarus) with bilateral isolated sensorineural hearing impairment were studied for the presence of mutations in the connexin 26 (GJB2) gene. Mutations were detected in 51 probands (46% of the sample). A significantly higher frequency of the GJB2 gene mutations was observed in familial cases of the disease with the autosomal recessive mode of inheritance (in 78% of families). Detected characteristics of the GJB2 gene mutation spectrum demonstrated that the using the algorithm, which was designed for Russian patients, is optimal for the molecular study of patients from Belarus. In the sample of patients with hearing loss, the highest (among other similar samples studied in the world) allele frequency of c.313_326del14 mutation (7% of all pathological GJB2 alleles) was registered; Polish origin of this deletion was suggested. It was demonstrated that detection of the GJB2 gene mutation on one patient’s chromosome only is insufficient to confirm a molecular genetic diagnosis of hearing loss of the DFNB1 genetic type (autosomal recessive hearing loss caused by the GJB2 gene mutations). Pilot screening for the GJB2 gene mutations in newborns from Grodno oblast was performed. The material from 235 children was studied during the screening; nine heterozygous carriers of the mutation were found. The c.35delG mutation was detected in a homozygous state in a single newborn (hearing loss of moderate severity was subsequently audiologically confirmed in this child).     

Congenitally defective aldosterone biosynthesis in humans: the involvement of point mutations of the P-450C18 gene (CYP11B2) in CMO II deficient patients.

The gene for steroid 18-hydroxylase (P-450C18) has been recently assigned to encode corticosterone methyl oxidases Type I and Type II which were previously postulated to catalyze the final two steps in the biosynthesis of aldosterone in humans. Molecular genetic analysis of the P-450C18 gene is three patients from three different families affected with CMO II deficiency has indicated that a point mutation of CGG----TGG (181Arg----Trp) in exon 3 and one of GTG----GCG (386Val----Ala) in exon 7 occur exclusively in the gene of the patients. Analysis of PCR products by restriction enzymes (HapII and HphI) has indicated that the patients are homozygous and the unaffected parent is heterozygous for both mutations, in accordance with the established concept that CMO II deficiency is inherited in an autosomal recessive manner. These data clearly provide the molecular genetic basis for the characteristic biochemical phenotype of CMO II clinical variants.     

Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation

Hereditary fructose intolerance (HFI) is a human autosomal recessive disease caused by a deficiency of aldolase B that results in an inability to metabolize fructose and related sugars. We report here the first identification of a molecular lesion in the aldolase B gene of an affected individual whose defective protein has previously been characterized. The mutation is a G----C transversion in exon 5 that creates a new recognition site for the restriction enzyme Ahall and results in an amino acid substitution (Ala----Pro) at position 149 of the protein within a region critical for substrate binding. Utilizing this novel restriction site and the polymerase chain reaction, the patient was shown to be homozygous for the mutation. Three other HFI patients from pedigrees unrelated to this individual were found to have the same mutation: two were homozygous and one was heterozygous. We suggest that this genetic lesion is a prevailing cause of hereditary fructose intolerance.     

Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia

Autosomal recessive forms of Charcot–Marie–Tooth disease (CMT) account for less than 10 % of all CMT cases, but are more frequent in the populations with a high rate of consanguinity. Roma (Gypsies) are a transnational minority with an estimated population of 10 to 14 million, in which a high degree of consanguineous marriages is a generally known fact. Similar to the other genetically isolated founder populations, the Roma harbour a number of unique or rare autosomal recessive disorders, caused by “private” founder mutations. There are three subtypes of autosomal recessive CMT with mutations private to the Roma population: CMT4C, CMT4D and CMT4G. We report on the molecular examination of four families of Roma origin in Slovakia with early-onset demyelinating neuropathy and autosomal recessive inheritance. We detected mutation p.R148X (g.631C>T) in the NDRG1 (NM_006096.3) gene in two families and mutation g.9712G>C in the HK1 (NM_033498) gene in the other two families. These mutations cause CMT4D and CMT4G, respectively. The success of molecular genetic analysis in all families confirms that autosomal recessive forms of CMT caused by mutations on the NDRG1 and HK1 genes are common causes of inherited neuropathies among Slovak Roma. Providing genetic analysis of these genes for patients with Roma origin as a common part of diagnostic procedure would contribute to a better rate of diagnosed cases of demyelinating neuropathy in Slovakia and in other countries with a Roma minority.     

Comparison of clinical parameters with whole exome sequencing analysis results of autosomal recessive patients; a center experience

Whole-exome sequencing (WES) is an ideal method for the diagnosis of autosomal recessive diseases. The aim of this study was to evaluate the diagnostic power of WES in patients with autosomal recessive inheritance and to determine the relationship between genotype and phenotype. Retrospective screenings of 24 patients analysed with WES were performed and clinical and genetic data were evaluated. Any pathogenic mutation that could explain the suspected disease in 4 patients was not identified. A homozygous pathogenic mutation was detected in 18 patients. 2 patients had heterozygous mutations. According to this study results, WES is a successful technique to be used at the stage of diagnosis in patients who are accompanied by various degrees of intellectual disability matching the inheritance of the autosomal recessive.

     

Founder effect and genetic disease in Sottunga, Finland

Pedigree data are analyzed in order to determine the factors responsible for the high frequencies of certain genetic disorders in an isolated Swedish-speaking population of Finland's A land archipelago. The founders of Sottunga are identified, and the genetic contributions of each founder to descending birth cohorts are estimated. Founders born before 1700 have far more descendants in the contemporary gene pool than do more recent founders. However, because of migration and depopulation since 1900, the expected genetic contributions of the early founders to the present-day population are similar to those of later founders. A descendant in the contemporary population has a 2% chance of having inherited a particular gene from the founder who makes the largest single contribution to the gene pool. This corresponds approximately to a 2% probability of inheriting an autosomal dominant disease gene from this founder. Given an average inbreeding coefficient of 0.0016, the probability of inheriting two recessive disease genes from this founder is 0.000032. The incidence of autosomal dominant von Willebrand disease in Sottunga is greater than 10% while that of autosomal recessive tapetoretinal disease is 1.5%. We conclude, therefore, that the high frequencies of these diseases are not due to the disproportionate genetic contribution of one or a few particular founders. It is more likely that these disease genes occurred in high frequency in the initial population or were introduced repeatedly through time.     

Evidence for nonallelic genetic heterogeneity in autosomal recessive retinitis pigmentosa.

Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal dominant retinitis pigmentosa. The availability of a unique inbred Dutch pedigree has enabled us to address this question. We have used an intragenic polymorphism to exclude the possibility that a mutation in the rhodopsin gene is responsible for the disease in this patient population. These data provide evidence for the involvement of at least two loci in autosomal recessively inherited retinitis pigmentosa.     

Utility and efficiency of linked marker genes for genetic counseling. II. Identification of linkage phase by offspring phenotypes

For a linked marker locus to be useful for genetic counseling, the counselee must be heterozygous for both disease and marker loci and his or her linkage phase must be known. It is shown that when the phenotypes of the counselee's previous children for the disease and marker loci are known, the linkage phase can often be inferred with a high probability, and thus it is possible to conduct genetic counseling. To evaluate the utility of linked marker genes for genetic counseling, the accuracy of prediction of the risk for a prospective child with a given marker gene to develop the genetic disease and the proportion of families in which a particular marker locus can be used for genetic counseling are studied for X-linked recessive, autosomal dominant, and autosomal recessive diseases. In the case of X-linked genetic diseases, information from children is very useful for determining the linkage phase of the counselee and predicting the genetic disease. In the case of autosomal dominant diseases, not all children are informative, but if the number of children is large, the phenotypes of children are often more informative than the information from grandparents. In the case of autosomal recessive diseases, information from grandparents is usually useless, since they show a normal phenotype for the disease locus. If we use information on the phenotypes of children, however, the linkage phase of the counselee and the risk of a prospective child can be inferred with a high probability. The proportion of informative families depends on the dominance relationship and frequencies of marker alleles, and the number of children. In general, codominant markers are more useful than are dominant markers, and a locus with high heterozygosity is more useful than is a locus with low heterozygosity.     

Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the<Emphasis Type="Italic"> TRKA (NTRK1)</Emphasis> gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis

Uniparental disomy (UPD) is defined as the presence of a chromosome pair that derives from only one parent in a diploid individual. The human TRKA gene on chromosome 1q21-q22 encodes a receptor tyrosine kinase for nerve growth factor and is responsible for an autosomal recessive genetic disorder: congenital insensitivity to pain with anhidrosis (CIPA). We report here the second case of paternal UPD for chromosome 1 in a male patient with CIPA who developed normally at term and did not show overt dysmorphisms or malformations. He had only the usual features of CIPA with a homozygous mutation at the TRKA locus and a normal karyotype with no visible deletions or evidence of monosomy 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome pair was exclusively derived from his father. Non-maternity was excluded by analyses of autosomes other than chromosome 1. Thus, we have identified a complete paternal isodisomy for chromosome 1 as the cause of reduction to homozygosity of the TRKA gene mutation, leading to CIPA. Our findings further support the idea that there are no paternally imprinted genes on chromosome 1 with a major effect on phenotype. UPD must be considered as a rare but possible cause of autosomal recessive disorders when conducting genetic testing.     

Identification of mutations in the uroporphyrinogen III cosynthase gene in German patients with congenital erythropoietic porphyria

The porphyrias are heterogeneous disorders arising from predominantly inherited catalytic deficiencies of specific enzymes along the heme biosynthetic pathway. Congenital erythropoietic porphyria is a very rare disease that is inherited as an autosomal recessive trait and results from a profound deficiency of uroporphyrinogen III cosynthase, the fourth enzyme in heme biosynthesis. The degree of severity of clinical symptoms mainly depends on the amount of residual uroporphyrinogen III cosynthase activity. In this study, we sought to characterize the molecular basis of congenital erythropoietic porphyria in Germany by studying four patients with congenital erythropoietic porphyria and their families. Using PCR-based techniques, we identified four different mutations: C73R, a well-known hotspot mutation, the promoter mutation -86A that was also described previously, and two novel missense mutations, designated G236V and L237P, the latter one encountered in the homozygous state in one of the patients. Our data from the German population further emphasize the molecular heterogeneity of congenital erythropoietic porphyria as well as the advantages of molecular genetic techniques as a diagnostic tool and for the detection of clinically asymptomatic heterozygous mutation carriers within families.     

Autosomal Dominant Postaxial Polydactyly, Nail Dystrophy, and Dental Abnormalities Map to Chromosome 4p16, in the Region Containing the Ellis–van Creveld Syndrome Locus

We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome.     

Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy.

Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explantation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (P = .09 +/- .06 for onset at 10-36 mo and .13 +/- .07 for onset at > 36 mo; and P = .09 +/- .07 for SMA IIIa and .12 +/- .07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given.     

A novel mutation in <Emphasis Type="Italic">RDH5</Emphasis> gene causes retinitis pigmentosa in consanguineous Pakistani family

Retinitis pigmentosa (RP) is the most frequent genetically and clinically heterogeneous inherited retinal degeneration. To date, more than 80 genes have been identified that cause autosomal dominant, autosomal recessive and X linked RP. However, locus and allelic heterogeneity of RP has not been fully captured yet. This heterogeneity and lack of an accurate genotype phenotype correlation makes molecular dissection of the disease more difficult. The present study was designed to characterize the underlying pathogenic variants of RP in Pakistan. For this purpose, a large consanguineous family with RP phenotype showing autosomal recessive mode of inheritance was selected after a complete ophthalmological examination. Next generation sequencing was used for the identification of molecular determinant followed by Sanger-sequencing for confirmation. After sequence analysis a novel homozygous missense mutation, (c.602 C?>?T) in exon 4 of the RDH5 gene (MIM: 601617) was identified. This mutation resulted in substitution of phenyl alanine for serine at amino acid 201 (p.Ser201Phe) of the RDH5 gene. The same mutation was not detected in the 200 ethnically-matched control samples by Sanger sequencing. The identified mutant allele segregated in homozygous fashion in all the affected individuals of pedigree. Identification of this mutation reveals the allelic heterogeneity of RDH5 in patients with RP phenotype. The findings of this study demonstrate the clinical significance of next generation sequencing to understand the molecular basis of diseases and would help to reveal new proteins and their function in visual cycle will pave the way for early diagnosis, genetic counseling and better therapeutic inventions.     

The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease

Brody disease is a rare inherited disorder of fast-twitch skeletal muscle function and is characterized by a lifelong history of exercise-induced impairment of skeletal muscle relaxation, stiffness, and cramps. The autosomal recessive inheritance of mutations in ATP2A1, the gene encoding SERCA1, which is the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, has been associated with Brody disease in three of six Brody families in which ATP2A1 has been sequenced. In the present analysis of the ATP2A1 gene in four unrelated families with autosomal recessive inheritance of Brody disease, three mutations were found in two families, leading to premature stop codons and truncated SERCA1. In a third family, the homozygous substitution of T for C2366 led to the missense mutation of Pro789 to Leu. The Pro789 to Leu mutant was readily expressed in HEK-293 cells, but it demonstrated an almost complete loss of Ca2+ transport activity because of reduced Ca2+ affinity. In a fourth family, the heterozygous substitution of T for C2455, mutating Arg819 to Cys, was identified. This mutation was also readily expressed in HEK-293 cells and shown to have near normal Ca2+ transport activity, indicating that it is not causal for Brody disease. These results confirm the genetic heterogeneity of Brody disease and emphasize the importance of a functional test for mutant SERCA1; immunostaining of skeletal muscle to detect the loss of SERCA1a protein is not adequate for the diagnosis of ATP2A1-linked Brody disease.     

Ascertainment and Prevention of Genetic Disease

A genetic register system has been developed for the ascertainment and prevention of genetic disease. Its potential value is illustrated with data collected from 478 families with serious genetic disorders which had been seen during the past five years. Of these 249 were referred specifically for genetic counselling, autosomal dominant disorders accounting for the largest group of families with individuals at high risk of becoming affected. Of 717 individuals at high risk of having affected children (or carrier daughters in the case of X-linked recessive disorders), only 101 were referred specifically for counselling. Many were referred only after the birth of an affected child which might otherwise have been prevented. A genetic register system linked to practitioner, hospital, and health department records could be a valuable means of preventing genetic disease.     

A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis

North American Indian childhood cirrhosis (CIRH1A, or NAIC), a severe autosomal recessive intrahepatic cholestasis described in Ojibway-Cree children from northwestern Quebec, is one of several familial cholestases with unknown molecular etiology. It typically presents with transient neonatal jaundice, in a child who is otherwise healthy, and progresses to biliary cirrhosis and portal hypertension. Clinical and physiological investigations have not revealed the underlying cause of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease. We previously identified the NAIC locus by homozygosity mapping to chromosome 16q22. Here we report that an exon 15 mutation in gene FLJ14728 (alias Cirhin) causes NAIC: c.1741C-->T in GenBank cDNA sequence NM_032830, found in all NAIC chromosomes, changes the conserved arginine 565 codon to a tryptophan, altering the predicted secondary structure of the protein. Cirhin is preferentially expressed in embryonic liver, is predicted to localize to mitochondria, and contains WD repeats, which are structural motifs frequently associated with molecular scaffolds.     

Ionizing radiation and genetic risks VII. The concept of mutation component and its use in risk estimation for Mendelian diseases

The responsiveness of Mendelian diseases to an increase in the mutation rate is studied by using the concept of the mutation component (MC) of genetic diseases. Algebraic expressions to evaluate MC at any specific generation following either a one-time or a permanent increase in mutation rate are derived and are illustrated with numerical examples. For a one-time increase in mutation rate, the analysis shows that the first generation MC for autosomal dominant diseases is equal to the selection coefficient; this is also true for X-linked diseases (adjusted for the proportion of X-chromosomes in males). For autosomal recessive diseases the first generation MC is substantially smaller than that for autosomal dominants. In subsequent generations MC gradually decays to zero. Under conditions of a permanent increase in the mutation rate, the MC for autosomal dominant, X-linked and completely recessive autosomal disorders progressively increases to reach a value of one at the new equilibrium. For incompletely recessive autosomal disorders, however, the MC at equilibrium can be larger than one. The rates of approach to the new equilibrium are different for the different classes of diseases, dictated by selection and time (in generations) following radiation exposure. The effects of increases in mutation rate on MC are more pronounced for autosomal dominants, followed by X-linked and are far less for autosomal recessives. Even for autosomal dominants, the early generation effects of radiation exposures would not be appreciable unless the heterozygotes have a severely reduced fitness.     

Spectrum of Mutations in the ATP7B Gene in Russian Patients with Wilson’s Disease

Russian Journal of Genetics - Wilson’s disease (WD) is an autosomal recessive disease caused by an excessive accumulation of copper. The molecular genetic etiology of the disease is due to...