Identified Compound Heterozygous Mutations Research Articles

A compound heterozygous mutation in the BSND gene detected in Bartter syndrome type IV

Bartter syndrome is a genetic disorder with hypokalemic metabolic alkalosis and is classified into five types. Type IV Bartter syndrome is a type of neonatal Bartter syndrome with sensorineural deafness and has been recently shown to be caused by mutations in the BSND gene. Owing to the rarity of this disease, only a limited number of mutations have been reported. We analyzed the BSND gene in a patient with type IV Bartter syndrome. The patient was delivered at 37 weeks, with normal body weight, and his neonatal course was uneventful. He was examined for developmental delay and polyuria at age 1 year 8 months and was found to have hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism, and sensorineural deafness. He developed end-stage renal failure at age 15 years, and renal transplantation was performed. We identified compound heterozygous mutations (Q32X and G47R) in the BSND gene. Each mutation was inherited from the parents. The Q32X mutation is a novel mutation and the first nonsense mutation identified in this gene. The mild perinatal clinical features of the patient were similar to those of a patient reported with a homozygous G47R mutation. However, the severity of renal failure suggested that factors other than this gene might affect the manifestation of renal abnormalities.

A Rare Case of Hypohidrotic Ectodermal Dysplasia Caused by Compound Heterozygous Mutations in the EDAR Gene

Hypohidrotic ectodermal dysplasia (HED) is a genetic disease characterized by abnormal hair, teeth, and sweat gland development. Although most cases of HED display X-linked recessive inheritance, autosomal dominant and autosomal recessive forms also exist. X-linked HED is caused by mutations in the EDA gene, and the autosomal forms result from mutations in either the EDAR gene or the EDARADD gene. In this study, we identified compound heterozygous mutations in the EDAR gene in a Japanese female patient with HED. On the maternal allele is a novel splice donor site mutation of intron 2 leading to the generation of unstable transcripts with exon 2 skipping; on the paternal allele is a novel R375H transition within the death domain of EDAR. Using expression studies in tissue culture cells, we found that the R375H substitution in EDAR caused loss of its affinity for EDARADD and reduced activation of the downstream target NF-kappaB. Our findings indicate that both alleles of EDAR are non-functional in our patient, resulting in the HED phenotype.

Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction and metaphyseal chondrodysplasia. SDS is caused by mutations in SBDS, an uncharacterized gene. A previous study in SDS patients largely of European ancestry found that most SBDS mutations occurred within a approximately 240-bp region of exon 2 and resulted from gene conversion due to recombination with a pseudogene, SBDSP. It is unknown, however, whether these findings are applicable to other ethnic groups. To address this question, we examined SBDS mutations in six Japanese families with SDS by direct sequencing. We identified compound heterozygous mutations in four families: two were recurrent (96-97insA, 258+2T>C), and three were novel [292-295delAAAG, (183-184TA>CT +201A>G), (141C>T+183-184TA>CT+201A>G)] mutations. Most of these mutations also appear to result from gene conversion, but the conversion events occurred at various sites between intron 1 and exon 3. Thus, gene conversion mutations in SBDS are common to different ethnic groups, but they are not confined to a limited region of the gene.

Evaluation of 50 probands with early-onset Parkinson’s disease for Parkin mutations

Early onset PD has been associated with different mutations in the Parkin gene, including exon deletions and duplications. The authors performed an extensive mutational analysis on 50 probands with onset of PD at younger than 50 years of age. Thirteen probands were ascertained from a registry of familial PD and 37 probands by age at onset at younger than 50 years, blind to family history. Mutational analysis was undertaken on the probands and available family members and included conventional techniques (single strand conformation polymorphism analysis and sequencing) and a newly developed method of quantitative duplex PCR to detect alterations of gene dosage (exon deletions and duplications) in PARKIN: Using this new technique, the authors detected eight alterations of gene dosage in the probands, whereas 12 mutations were found by conventional methods among the probands and another different mutation in an affected family member. In total, the authors identified compound heterozygous mutations in 14%, heterozygous mutations in 12%, and no Parkin mutation in 74% of the 50 probands. We expanded the occurrence of Parkin mutations to another ethnic group (African-American). The authors systematically screened all 12 Parkin exons by quantitative PCR and conventional methods in 50 probands. Eight mutations were newly reported, 2 of which are localized in exon 1, and 38% of the mutations were gene dosage alterations. These results underline the need to screen all exons and to undertake gene dosage studies. Furthermore, this study reveals a frequency of heterozygous mutation carriers that may signify a unique mode of inheritance and expression of the Parkin gene.

Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension.

Gitelman's syndrome is an autosomal recessive disorder characterized by electrolyte disturbances and low blood pressure. The disease is caused by homozygous or compound heterozygous inactivating mutations in the thiazide-sensitive NaCl-cotransporter gene leading to reduced renal sodium reabsorption. We report 4 patients with Gitelman's syndrome from southern Sweden, all in whom we identified compound heterozygous mutations in the thiazide-sensitive NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hypothesized that such mutations in their heterozygous form protect against primary hypertension in the general population and that the gene may also harbor activating mutations that increase the risk for primary hypertension. Accordingly, the gene was screened for mutations in 20 patients with primary hypertension and in 20 normotensive subjects by single-strand conformation polymorphism and direct DNA sequencing. The Arg904Gln, Gly264Ala, and C1420T variants, found in the mutation screening of subjects without Gitelman's syndrome, were studied further. Population genotype frequencies were determined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overrepresented in hypertensive patients compared with normotensive subjects (5 of 292 versus 0 of 264; P:=0.03). In conclusion, we confirm that Gitelman's syndrome is caused by mutations in the thiazide-sensitive NaCl-cotransporter gene. Our results further suggest that subjects homozygous for the Gln904 variant have an increased risk for development of primary hypertension.