A Turkish patient with novel AHCY variants and presumed diagnosis of S‐adenosylhomocysteine hydrolase deficiency

S‐adenosylhomocysteine hydrolase deficiency is an autosomal recessive neurometabolic disorder affecting the muscles, liver, and nervous system. The disease occurs by pathogenic variants of AHCY gene encoding S‐adenosylhomocysteine hydrolase (AHCY) enzyme. This article reports a patient with presumed AHCY deficiency who was diagnosed by whole exome sequencing due to compound heterozygosity of novel p.T57I (c.170C>T) and p.V217M (c.649G>A) variants of AHCY gene. The patient had diffuse edema, coagulopathy, central nervous system abnormalities, and hypotonia. She died in 3 months due to cardiovascular collapse. Clinical findings of the present case were compatible with previously reported AHCY deficiency patients and the novel variants we found are considered to be the cause of the symptoms. This article also compiles the previous reports and expands clinical spectrum of AHCY deficiency by adding new features.     

Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH)

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary genodermatosis characterized by hyperpigmented and hypopigmented macules of on the extremities and caused by the mutations in the ADAR gene(also called DSRAD) encoding for RNA-specific adenosine deaminase. Here we reported clinical and molecular findings of 6 Chinese multi-generation families and 2 sporadic patients with DSH. We found that the same mutation could lead to different phenotypes even in the same family and we did not establish a clear correlation between genotypes and phenotypes. Seven novel heterozygous mutations of ADAR were identified, which were c.2433_2434delAG (p.T811fs), c.2197G>T (p.E733X), c.3286C>T (p.R1096X), c.2897G>T (p.C966F), c.2797C>T (p.Q933X), c.2375delT (p.L792fs) and c.3203-2A>G respectively. Our data add new variants to the repertoire of ADAR mutations in DSH.     

Genotype‐phenotype study in patients with valosin‐containing protein mutations associated with multisystem proteinopathy

Mutations in valosin‐containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Approximately 9% of patients with VCP mutations had an amyotrophic lateral sclerosis (ALS) phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large interfamilial and intrafamilial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared with other molecular subtypes.     

FOXE3 mutations: genotype‐phenotype correlations

Microphthalmia and anophthalmia (MA) are severe developmental eye anomalies, many of which are likely to have an underlying genetic cause. More than 30 genes have been described, each of which is responsible for a small percentage of these anomalies. Among these, is the FOXE3 gene, which was initially described in individuals with dominantly inherited anterior segment dysgenesis and, subsequently, associated with recessively inherited primary aphakia, sclerocornea and microphthalmia. In this work, we describe 8 individuals presenting with an MA phenotype. Among them, 7 are carrying biallelic recessive FOXE3 mutations and 2 of these have novel mutations: p.(Ala78Thr) and p.(Arg104Cys). The last of our patients is carrying in the heterozygous state the recessive p.(Arg90Leu) mutation in the FOXE3 gene. To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. Furthermore, understanding the genetic basis of these conditions will contribute to overall understanding of eye development, improve the quality of care, genetic counseling and, in future, gene‐based therapies.     

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

Mitochondrial acetoacetyl‐CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. It typically manifests with episodic ketoacidosis. The presence of isoleucine‐derived metabolites is the key marker for biochemical diagnosis. To date, 105 ACAT1 variants have been reported in 149 T2‐deficient patients. The 56 disease‐associated missense ACAT1 variants have been mapped onto the crystal structure of T2. Almost all these missense variants concern residues that are completely or partially buried in the T2 structure. Such variants are expected to cause T2 deficiency by having lower in vivo T2 activity because of lower folding efficiency and/or stability. Expression and activity data of 30 disease‐associated missense ACAT1 variants have been measured by expressing them in human SV40‐transformed fibroblasts. Only two variants (p.Cys126Ser and p.Tyr219His) appear to have equal stability as wild‐type. For these variants, which are inactive, the side chains point into the active site. In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype. This could be related to variable remaining residual T2 activity in vivo and has important clinical implications concerning disease management and newborn screening.     

Characterization of new arylsulfatase A gene mutations reinforces genotype‐phenotype correlation in metachromatic leukodystrophy

Metachromatic Leukodystrophy (MLD) is a rare inherited lysosomal storage disorder caused by the deficiency of Arylsulfatase A (ARSA). The disease manifests itself with a broad spectrum of clinical variants, all characterized by progressive neurodegeneration in the central and peripheral nervous systems. The correlation between mutations in the ARSA gene, residual enzymatic activity associated with the mutated alleles and patients' phenotype, which has been extensively drawn for common ARSA mutations, has recently been expanded to rare ones. In this context, functional studies on the rare allelic variances acquire particular relevance for patients' prognostic evaluation. Here we have characterized eight newly identified ARSA mutations, through lentiviral vector‐based expression studies on cell lines and ARSA defective murine fibroblasts. In each case, the residual activity associated with the new mutant allele correlates well with the patient's phenotype. Therefore, our results confirm the importance of functional characterization of mutant alleles for a precise genotype‐based classification and definition of prognosis in MLD patients, which is particularly relevant for pre‐symptomatic diagnosis. © 2009 Wiley‐Liss, Inc.     

Comprehensive genotype‐phenotype correlation in AP‐4 deficiency syndrome; Adding data from a large cohort of Iranian patients

Mutations in adaptor protein complex‐4 (AP‐4) genes have first been identified in 2009, causing a phenotype termed as AP‐4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype‐phenotype correlation of the AP‐4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease‐causing variants in AP‐4 complex subunits, using next‐generation sequencing. Furthermore, by comparing genotype‐phenotype findings of those affected individuals with previously reported patients, we further refine the genotype‐phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP‐4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders.     

Relationship of impairment induced by intracellular S‐adenosylhomocysteine accumulation with DNA methylation in human umbilical vein endothelial cells treated with 3‐deazaadenosine

The aim of this study was to estimate the relationship of endothelial dysfunction induced by intracellular S-adenosylhomocysteine (SAH) accumulation and DNA methylation in human umbilical vein endothelial cells (HUVEC). The isolated HUVEC were incubated with 3-deazaadenosine (DZA) to induce experimental intracellular SAH accumulation. The impairment of HUVEC function was assessed by changes in morphology and proliferative ability. The expression of DNA methyltransferase-1 (DNMT1) and the atherosclerosis related genes [oestrogen receptor-alpha (ER-α), extracellular superoxide dismutase (EC-SOD) and monocyte chemoattractant protein-1 (MCP-1)] were analysed using quantitative real-time PCR. Global DNA methylated status was measured using the cytosine extension assay. The methylated patterns of ER-α, EC-SOD and MCP-1 genes were determined with methylation-specific PCR. We found that DZA administration increased intracellular SAH levels progressively and simultaneously decreased Hcy content in medium. Moreover, the supplementation induced HUVEC apoptosis, inhibited proliferation ability and DNMT1 mRNA expression (P<0.05) and furthermore reduced global DNA methylation status (P<0.05). Correlation analysis showed the presence of a negative correlation between intracellular SAH concentration, proliferative ability, and expression of ER-α, EC-SOD, and DNMT1 (r = −0.89, −0.86, −0.92 and −0.88 respectively, P<0.001); and a positive correlation with MCP-1 expression and DNA [³H]-dCTP incorporation (r = 0.89 and 0.93 respectively, P<0.001). Our results showed that endothelial dysfunction induced by intracellular SAH accumulation is mediated by regulating the expression of atherosclerosis related genes in HUVEC, which is not related with gene promoter methylated patterns, but may be associated with altered global DNA hypomethylated status. These findings suggest that SAH can act as the potential molecular biological marker in the promotion of atherogenesis.     

Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1)

Recently, the polyglutamine-binding protein 1 (PQBP1) gene was found to be mutated in five of 29 families studied with X-linked mental retardation (XLMR) linked to Xp. The reported mutations include duplications or deletions of AG dinucleotides in the fourth coding exon that resulted in shifts of the open reading frame. Three of the five families with mutations in this newly identified XLMR gene have been reported previously. We characterized the phenotypic and neuropsychological features in the two unpublished families with aberrations in PQBP1 and in a family reported 10 years ago. In total, seven patients diagnosed with aberrations in this gene were examined, including a newly identified patient at 18 months of age. Additionally, the features were compared to those reported in the literature of three other families, comprising MRXS3 (Sutherland-Haan syndrome) MRX55 and MRXS8 (Renpenning syndrome). Characteristics seen in these patients are microcephaly, lean body habitus, short stature, striking facial appearance with long narrow faces, upward slant of the eyes, malar hypoplasia, prognathism, high-arched palate and nasal speech. In addition, small testes and midline defects as anal atresia or imperforate anus, clefting of palate and/or uvula, iris coloboma and Tetralogy of Fallot are seen in several patients. These observations contribute to the phenotypic knowledge of patients with PQBP1 mutations and make this XLMR syndrome well recognizable to clinicians.     

UMD‐CFTR: A database dedicated to CF and CFTR‐related disorders

With the increasing knowledge of cystic fibrosis (CF) and CFTR‐related diseases (CFTR‐RD), the number of sequence variations in the CFTR gene is constantly raising. CF and particularly CFTR‐RD provide a particular challenge because of many unclassified variants and identical genotypes associated with different phenotypes. Using the Universal Mutation Database (UMD^®) software we have constructed UMD‐CFTR (freely available at the URL: http://www.umd.be/CFTR/ ), the first comprehensive relational CFTR database that allows an in‐depth analysis and annotation of all variations identified in individuals whose CFTR genes have been analyzed extensively. The system has been tested on the molecular data from 757 patients (540 CF and 217 CBAVD) including disease‐causing, unclassified, and nonpathogenic alterations (301 different sequence variations) representing 3,973 entries. Tools are provided to assess the pathogenicity of mutations. UMD‐CFTR also offers a number of query tools and graphical views providing instant access to the list of mutations, their frequencies, positions and predicted consequences, or correlations between genotypes, haplotypes, and phenotypes. UMD‐CFTR offers a way to compile not only disease‐causing genotypes but also haplotypes. It will help the CFTR scientific and medical communities to improve sequence variation interpretation, evaluate the putative influence of haplotypes on mutations, and correlate molecular data with phenotypes. Hum Mutat 31:1011–1019, 2010. © 2010 Wiley‐Liss, Inc.     

Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: Haplotype and genotype–phenotype correlation studies in spanish metachromatic leukodystrophy patients

Arylsulfatase A (ARSA) deficiency is the main cause of metachromatic leukodystrophy (MLD), a lysosomal disorder with no specific treatment. In view of the importance of genetic counseling, analyses of mutations and polymorphisms, including the ARSA pseudodeficiency allele, were carried out in 18 unrelated Spanish MLD patients. A systematic search allowed us to identify 100% of the alleles involving 17 different mutations, 12 of which are novel: G32S, L68P, R84W, P94A, G99V, P136S, W193X, H227Y, R288H, G308D, T327I, and IVS6‐12C→G. Two new polymorphisms, 2033C>T and 2059C>T, were identified in intron 6 which, in combination with two polymorphisms previously described (2161C>G and 2213C>G), gave rise to four different haplotypes in the control population. In addition, we also studied polymorphism 842G>T. Linkage disequilibrium was detected between mutations IVS2+1G→A, D255H, and T327I and specific haplotypes, suggesting a unique origin for these mutations. Moreover, mutation T327I was always associated with the T allele of the new rare variant A210A (893C>T). The distribution of mutation D255H (frequency 19.4%) among patients with different MLD clinical presentation revealed a clear genotype–phenotype correlation paralleling that reported for mutation IVS2+1G→A (frequency 25%). Among the novel mutations, only P136S and R288H occurred on a background of the ARSA pseudodeficiency allele. Screening 182 normal chromosomes identified a frequency of 8.8% of this allele; moreover, we identified two unrelated subjects with the polyA‐ mutation in the absence of the N350S mutation, and this infrequent haplotype reinforced the heterogeneity of conditions with ARSA deficiency. Hum Mutat 14:240–248, 1999. © 1999 Wiley‐Liss, Inc.     

Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: Report of 14 novel mutations and review of the literature

Beals‐Hecht syndrome or congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disorder characterized by crumpled ears, arachnodactyly, contractures, and scoliosis. Recent reports also mention aortic root dilatation, a finding previously thought to differentiate the condition from Marfan syndrome (MFS). In many cases, the condition is caused by mutations in the fibrillin 2 gene (FBN2) with 26 mutations reported so far, all located in the middle region of the gene (exons 23–34). We directly sequenced the entire FBN2 gene in 32 probands clinically diagnosed with CCA. In 14 probands, we found 13 new and one previously described FBN2 mutation including a mutation in exon 17, expanding the region in which FBN2 mutations occur in CCA. Review of the literature showed that the phenotype of the FBN2 positive patients was comparable to all previously published FBN2‐positive patients. In our FBN2‐positive patients, cardiovascular involvement included mitral valve prolapse in two adult patients and aortic root enlargement in three patients. Whereas the dilatation regressed in one proband, it remained marked in a child proband (z‐score: 4.09) and his father (z‐score: 2.94), warranting echocardiographic follow‐up. We confirm paradoxical patellar laxity and report keratoconus, shoulder muscle hypoplasia, and pyeloureteral junction stenosis as new features. In addition, we illustrate large intrafamilial variability. Finally, the FBN2‐negative patients in this cohort were clinically indistinguishable from all published FBN2‐positive patients harboring a FBN2 mutation, suggesting locus heterogeneity. Hum Mutat 0, 1–8, 2008. © 2008 Wiley‐Liss, Inc.     

Dihydropteridine reductase deficiency: Physical structure of the QDPR gene,identification of two new mutations and genotype–phenotype correlations

Dihydropteridine reductase (DHPR) is an enzyme involved in recycling of tetrahydrobiopterin (BH₄), the cofactor of the aromatic amino acid hydroxylases. Its deficiency is characterized by hyperphenylalaninemia due to the secondary defect of phenylalanine hydroxylase and depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases. The DHPR cDNA has been cloned and mapped on 4p15.3. In the present study we report the genomic structure of the DHPR gene (QDPR). This gene includes seven exons within a range of 84–564 bp; the corresponding introns are flanked by canonic splice junctions. We also present a panel of PCR primers complementary to intronic sequences that greatly facilitates amplification of the gene and provides a genomic DNA approach for mutation detection. We have used this approach to study six patients with DHPR deficiency. Four known mutations (G23D, H158Y, IVS5G + 1A, R221X) and two new mutations (Y150C and G218ins9bp) were found. The Y150C mutation was found in compound heterozygosity with G23D, a mutation always associated with a severe phenotype in homozygous patients. This patient has an intermediate phenotype (good response to monotherapy with BH₄). The mutant enzyme for Y150C was expressed in an E. coli system. Comparison of its kinetic parameters with those of the G23D mutant enzyme showed that it is not as effective as the wild-type enzyme, but is more active than the G23D mutant. This patient's intermediate phenotype is thus due to the mild DHPR mutation Y150C. Correlations between genotypes and phenotypes were also found for the other mutations. Hum Mutat 12:267–273, 1998. © 1998 Wiley-Liss, Inc.     

Richieri‐Costa‐Pereira syndrome: Expanding its phenotypic and genotypic spectrum

Richieri‐Costa‐Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5′ untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14‐repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri‐Costa‐Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16‐repeat expansion in EIF4A3, there was an overrepresentation of the 14‐repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.     

Two novel fibrillin‐2 mutations in congenital contractural arachnodactyly

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder, comprising marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. It is now known that mutations in the gene encoding fibrillin‐2 cause CCA. Interestingly, mutations described to date cluster in the fibrillin‐2 region homologous to the so‐called neonatal Marfan syndrome region of fibrillin‐1. Thus, it has been hypothesized that the relative infrequency of CCA compared with the Marfan syndrome is due to the limited region of the gene targeted for mutations. In support of the above hypothesis, we report here the finding of two additional FBN2 mutations in CCA, C1141F (exon 26) and C1252W (exon 29). In addition, a new 3′ UTR polymorphism is also described. Am. J. Med. Genet. 92:7–12, 2000. © 2000 Wiley‐Liss, Inc.     

Acid sphingomyelinase: identification of nine novel mutations among Italian Niemann Pick type B patients and characterization of in vivo functional in-frame start codon

Niemann Pick disease (NPD) is an autosomal recessive disorder due to the deficit of lysosomal acid sphingomyelinase, which results in intracellular accumulation of sphingomyelin. In the present work we studied 18 patients with NPD type B, including five individuals who presented an intermediate phenotype characterised by different levels of neurological involvement. We identified nine novel mutations in the SMPD1 gene including six single base changes c.2T>G, c.96G>A, c.308T>C, c.674T>C, c.732G>C, c.841G>A (p.M1_W32del, p.W32X, p.L103P, p.L225P, p.W244C, p.A281T) and three frameshift mutations c.100delC, c.565dupC, c.575dupC (p.G34fsX42, p.P189fsX1 and p.P192fsX14). The novel c.2T>G (p.M1_W32del) mutation inactivates the first in-frame translation start site of the SMPD1 gene and in the homozygous status causes NPD type B indicating that in'vivo translation of wild type SMPD1 initiates from the first in-frame ATG. Moreover, the new c.96G>A (p.W32X) introduces a premature stop codon before the second in-frame ATG. As a consequence of either c.2T>G (p.M1_W32del) or c.96G>A (p.W32X), impaired translation from the first in-frame ATG results in a mild NPD-B phenotype instead of the severe phenotype expected for a complete deficiency of the enzyme, suggesting that when the first ATG is not functional, the second initiation codon (ATG33) still produces a fairly functional sphingomyelinase. Analysis of the patients'clinical and molecular data demonstrated that all five patients with the intermediate phenotype carried at least one severe mutation. No association between the onset of pulmonary symptoms and genotype was observed. Finally, the presence of c.96G>A (p.W32X), the most frequent allele among Italian NPD type B population, and c.1799G>C (p.R600P) as compound heterozygotes in association with severe mutations suggested a beneficial effect for both mutations.     

MUTYH‐associated polyposis – variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations

Morak M, Laner A, Bacher U, Keiling C, Holinski‐Feder E. MUTYH‐associated polyposis – variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. To further characterize 215 APC mutation‐negative patients with colorectal neoplasias classified in classical, attenuated, or atypical familial adenomatous polyposis (FAP) coli we performed mutation screening in the Mut Y homologue (MUTYH) gene. The incidence was 15% for biallelic and 3.7% for monoallelic MUTYH mutations. We describe six novel MUTYH mutations in biallelic constellation and two novel monoallelic missense mutations. Of 33 MUTYH‐associated polyposis coli (MAP) patients 57% were attenuated familial adenomatous polyposis (AFAP) patients, 10% display early‐onset classical FAP and 18% had only few adenomas at higher age. Biallelic cases had a high incidence of extracolonic polyposis in 32% and colorectal cancer (CRC) in 33% of the cases. The clinical picture of MAP ranged from classical FAP or synchronous CRC at age 30 years to few adenomas at age 54 years without evidence of CRC, initially suspected for hereditary non‐polyposis colorectal cancer (HNPCC). The mean age of onset was 43 years, with 11 (33%) patients being younger than 40 years of age, indicating that the clinical manifestation can be earlier than so far reported. Monoallelic MUTYH mutation carriers had a positive family history in seven of eight cases allowing the hypothesis of a disease‐causing synergism of MUTYH mutations with other genes.     

蒙古族X连锁先天缺失牙/头发卷曲家系EDA基因新错义突变的发现

为鉴定蒙古族X连锁先天缺失牙／头发卷曲家系外胚层发育不全无汗综合征致病基因(EDA)突变类型及其与表型的关系,本文以七代患有先天缺失牙的蒙古族大家系为研究对象,应用聚合酶链反应产物直接测序(PCR／Sequencing)分析每个成员EDA基因第一外显子碱基突变及其部位。测序结果显示,先证者及其他男性患者EDA基因第一外显子193位的胞嘧啶被鸟嘌呤取代,均为193G／G纯合基因型,193C→G颠换是一种新的错义突变,导致胞外区65精氨酸转变为甘氨酸(R65G)。先症者母亲Ⅳ8为193C／G杂合基因型,牙齿正常。携带193G／C杂合基因型女性临床表型为Ⅴ3表现11、21、31、41缺如,Ⅴ31表现12、22缺如,两者均伴有头发卷曲,而Ⅴ1、Ⅴ6、Ⅴ8、Ⅴ11、Ⅴ20、Ⅴ46及Ⅳ10、Ⅵ3等牙齿数目及形态均无明显异常,头发无卷曲。综上所述,该蒙古族大家系中EDA基因第一外显子193位C→G颠换引起的错义突变,是导致其发病的主要分子机制之一。但携带193G突变等位基因杂合基因型女性表型各异以及男性患者表现度不一致的机制有待深入研究。