Mutation Analysis of<i>SLC7A9</i>in Cystinuria Patients in Sweden

Harnevik, Lotta; Fjellstedt, Erik; Molbaek, Annette; Denneberg, Torsten; Söderkvist, Peter

doi:10.1089/109065703321560886

Cited by 39 publications

(26 citation statements)

References 28 publications

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“…One patient AA(B) has previously been reported but with no description of the associated urine phenotype. 37 The degree of aminoaciduria of these type of patient and their relatives in the ICC database indicates that digenic inheritance in cystinuria has only a partial effect on the phenotype, restricted to a variable impact on the aminoaciduria, for the following reasons.…”

Section: Discussionmentioning

confidence: 99%

New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype

Font-Llitjós

Jiménez-Vidal

Bisceglia

et al. 2005

Journal of Medical Genetics

149

126

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Objective: To clarify the genotype-phenotype correlation and elucidate the role of digenic inheritance in cystinuria. Methods: 164 probands from the International Cystinuria Consortium were screened for mutations in SLC3A1 (type A) and SLC7A9 (type B) and classified on the basis of urine excretion of cystine and dibasic amino acids by obligate heterozygotes into 37 type I (silent heterozygotes), 46 type non-I (hyperexcretor heterozygotes), 14 mixed, and 67 untyped probands. Results: Mutations were identified in 97% of the probands, representing 282 alleles (86.8%). Forty new mutations were identified: 24 in SLC3A1 and 16 in SLC7A9. Type A heterozygotes showed phenotype I, but mutation DupE5-E9 showed phenotype non-I in some heterozygotes. Type B heterozygotes showed phenotype non-I, with the exception of 10 type B mutations which showed phenotype I in some heterozygotes. Thus most type I probands carried type A mutations and all type non-I probands carried type B mutations. Types B and A mutations contributed to mixed type, BB being the most representative genotype. Two mixed cystinuria families transmitted mutations in both genes: double compound heterozygotes (type AB) had greater aminoaciduria than single heterozygotes in their family. Conclusions: Digenic inheritance is an exception (two of 164 families), with a limited contribution to the aminoaciduria values (partial phenotype) in cystinuria. Further mutational analysis could focus on one of the two genes (SLC3A1 preferentially for type I and SLC7A9 for type non-I probands), while for mixed probands analysis of both genes might be required, with priority given to SLC7A9.

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Section: Discussionmentioning

confidence: 99%

New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype

Font-Llitjós

Jiménez-Vidal

Bisceglia

et al. 2005

Journal of Medical Genetics

149

126

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“…The mutation p.Tyr151Cys has mainly been observed in Northern Europe [34]. The duplication dupE5E9 might have occurred from a German founder, however data are limited as tests aiming on larger genomic imbalances were not routinely applied for cystinuria diagnostics in the past.…”

Section: Genetics and Spectrum Of Mutationsmentioning

confidence: 99%

Cystinuria: an inborn cause of urolithiasis

Eggermann

Venghaus

Zerres

2012

Orphanet J Rare Dis

102

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Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b0,+ transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b0,+AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.

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“…Cohorts of patients from Europe, Asia, and North America have been genotyped (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) along with a recently published group of United Kingdom patients (22).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Rhodes

Yarram-Smith²,

Rice

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Cystinuria is a rare inherited renal stone disease. Mutations in the amino acid exchanger System b 0,+ , the two subunits of which are encoded by SLC3A1 and SLC7A9, predominantly underlie this disease. The work analyzed the epidemiology of cystinuria and the influence of mutations in these two genes on disease severity in a United Kingdom cohort.Design, setting, participants, & measurements Prevalent patients were studied from 2012 to 2014 in the northeast and southwest of the United Kingdom. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 combining Sanger sequencing and multiplex ligation probe-dependent amplification was performed.Results In total, 76 patients (42 men and 34 women) were studied. All subjects had proven cystine stones. Median age of presentation (first stone episode) was 24 years old, but 21% of patients presented after 40 years old. Patients had varied clinical courses, with 37% of patients having $10 stone episodes; 70% had evidence of CKD, and 9% had reached ESRD as a result of cystinuria and its complications. Patients with cystinuria received a variety of different therapies, with no obvious treatment consensus. Notably, 20% of patients had staghorn calculi, with associated impaired renal function in 80% of these patients. Genetic analysis revealed that biallelic mutations were present in either SLC3A1 (n=27) or SLC7A9 (n=20); 22 patients had only one mutated allele detected (SLC3A1 in five patients and SLC7A9 in 17 patients). In total, 37 different mutant variant alleles were identified, including 12 novel mutations; 22% of mutations were caused by large gene rearrangements. No genotypephenotype association was detected in this cohort.Conclusions Patients with cystinuria in the United Kingdom often present atypically with staghorn calculi at $40 years old and commonly develop significant renal impairment. There is no association of clinical course with genotype. Treatments directed toward reducing stone burden need to be rationalized and developed to optimize patient care.

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Mutation Analysis ofSLC7A9in Cystinuria Patients in Sweden

Cited by 39 publications

References 28 publications

New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype

New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype

Cystinuria: an inborn cause of urolithiasis

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

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