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

Abstract

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.

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

“…The deletion of exon 12 accounts for 11% of SLC7A9 alleles in this study but was not described in the recent United Kingdom study (22). Previous cystinuria studies have focused on different clinical aspects of this disease, but many have analyzed genotype-phenotype associations (5,6,11,15,18,22,(36)(37)(38). These are summarized in Table 7.…”

“…Patients with mutations in SLC3A1 are known as type A, and those with SLC7A9 are known as type B. Genotype types AA and BB denote two mutated alleles in SLC3A1 or SLC7A9, respectively, whereas A and B denote the identification of only one mutated allele (5). In a third rare group, type AB, individuals have one mutation in SLC3A1 and one mutation in SLC7A9 (6).…”

“…In a third rare group, type AB, individuals have one mutation in SLC3A1 and one mutation in SLC7A9 (6). Occasionally, there are more than two mutated alleles present, such as AAB and BBA (5).…”

Global distribution of the most prevalent deletions causing hypotonia–cystinuria syndrome

“…Possibly, two other alleles exist, but the break points have not been determined. 7,8 In conclusion, HCS is a relatively homogenous syndrome, with common ancestral alleles found in different populations. On the basis of the allele frequencies, this disease will be rare (1/1 000 000 for an allele frequency of 1/1000); hence, our observations are compatible with a founder effect in the regions from where the HCS patients originate.…”

Chromosomal Microdeletions and Genes' Functions: A cluster of chromosomal microdeletions and the deleted genes' functions

“…Inactivation of this gene product is known to cause isolated cystinuria type I. 8 The other clinical features of the HCS can therefore be attributed to the gene product of PREPL. Thus the absence of the PREPL gene causes neonatal and infantile hypotonia, and poor feeding during infancy, often necessitating nasogastric tube feeding or gastrostomy.…”