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Lysinuric protein intolerance

Lysinuric protein intolerance (LPI), also named hyperdibasic aminoaciduria type 2 or familial protein intolerance (MIM 222700), is an autosomal recessive disorder of diamino acid transport. About 100 patients have been reported, almost half of them of Finnish origin. more...

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Lysinuric protein...


In LPI, urinary excretion of cationic amino acids (ornithine, arginine and lysine) is increased and these amino acids are poorly absorbed from the intestine. Therefore, their plasma concentrations are low and their body pools become depleted. Deficiency of arginine and ornithine restricts the function of the urea cycle and leads to hyperammonemia after protein-rich meals. Deficiency of lysine may play a major role in the skeletal and immunological abnormalities observed in LPI patients.


The diagnosis is based on the biochemical findings (increased concentrations of lysine, arginine and ornithine in urine and low concentrations of these amino acids in plasma, elevation of urinary orotic acid excretion after protein-rich meals, and inappropriately high concentrations of serum ferritin and lactate dehydrogenase isoenzymes) and the screening of known mutations of the causative gene from a DNA sample.


Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning. The patients show failure to thrive, poor appetite, growth retardation, enlarged liver and spleen, prominent osteoporosis, delayed bone age and spontaneous protein aversion. Forced feeding of protein may lead to convulsions and coma. Mental development is normal if prolonged episode of hyperammonemia can be avoided. Some patients develop severe pulmonary and renal complications.

Treatment and prognosis

Treatment of LPI consists of protein-restricted diet and supplementation with oral citrulline. Citrulline is a neutral amino acid that improves the function of the urea cycle and allows sufficient protein intake without hyperammonemia. Under proper dietary control and supplementation, the majority of the LPI patients are able to have a nearly normal life.


Simell, O et al: Lysinuric protein intolerance. Am J Med. 1975 Aug;59(2):229-40, .


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A historical aspect of lysinuric protein intolerance in a Northern part of Iwate, Japan
From Human Biology, 2/1/03 by Inoue, Yusuke

Abstract Historical aspects of a local cluster of individuals with lysinuric protein intolerance (LPI) were studied in a sample of patients and in a mass-screened population in a northern area of Japan. The historical aspects were investigated by estimating the mutation age and analyses of haplotype diversity of the chromosome carrying the R410X mutation. This mutation occurred over 1000 years ago, and its fixation in the local cluster suggests that LPI had been a nearly neutral phenotype. The present results also give an estimate of the geographical distribution of the R410X mutation, providing a basis for targeting populations for mass screening for LPI.


Lysinuric protein intolerance (LPI: MIM#222700) is an autosomal recessive disease characterized by defective transport of the dibasic amino acids. It has recently been shown that the SLC7A7 gene encodes the transporter of dibasic amino acids, mutations of which cause LPI (Borsani et al. 1999; Torrents et al. 1999). Patients with LPI are usually symptom-free in infancy, after which they reject high-protein foods, grow poorly, and exhibit an enlarged liver and spleen, muscle hypotonia, and sparse hair (Simell et al. 1975). Osteoporosis and growth retardation also occur (Simell et al. 1975). The prognosis for mental development varies from normal development to moderate retardation (Simell 2001). Some patients develop potentially fatal complications including pulmonary involvement, renal insufficiency, and immunological abnormalities (DiRocco et al. 1993; Kamoda et al. 1998).

LPI was first described in Finnish patients in 1965 (Perheentupa and Visakorpi 1965). The disease shows a worldwide distribution; however, localized clusters have been reported in Finland (33 families), southern Italy (Incerti et al. 1993), and Japan (Kato et al. 1984).

We report a local cluster of LPI in a northern part of Iwate that had an estimated population prevalence of 1:60,000 births, which is comparable to that reported for the Finnish cluster (Koizumi et al. 2000). Mutational analysis of SLC7A7 revealed a founder mutation, R410X, in patients in this cluster (Noguchi et al. 2000; Koizumi et al. 2000).

Detection of homozygotes of the R410X mutation at an early age, followed by early initiation of citrulline therapy and protein restriction, can improve clinical outcomes significantly. It was for this reason that a mass-screening program for newborn babies was initiated in a northern part of the Iwate area beginning in July 1999.

The aim of the present study is to investigate historical aspects of LPI in the northern part of Iwate. These aspects were investigated by estimating the mutation age and analyses of haplotype diversity of the chromosome carrying the R410X mutation.

Materials and Methods

Experimental Design. In the previous study, an 18-base-pair (bp) region in intron 8, tentatively named allele B (wild type: allele A), was found to have a linkage disequilibrium with the R410X mutation (Koizumi et al. 2000). We estimated the ages of R410X and allele B mutations from haplotype diversity of two microsatellite markers surrounding SLC7A7, D14S990 (recombination fraction [theta] = 0.00329 from SLC7A7) and D14S283 (recombination fraction [theta] = 0.00577 from SLC7A7). The estimation was done using DNA samples from mass screening participants. The frequencies of allele B outside the mass screened area were determined using DNA samples donated from residents in Tokushima and Akita (Figure 1).

Population. Eight probands in eight pedigrees found in Iwate and 23 heterozygotes detected in the mass screening in Iwate were used in this study. One of the probands had a father who was originally from the Gifu area in the middle of Japan (Figure 1). All probands have clinical symptoms of LPI with the typical hyperdiaminoaciduria and hyperammonemic response to an intravenous loading test. Parents of 23 heterozygous participants also participated in this study.

Allele frequencies for D14D990, D14S283, and intron 8 of SLC7A7 were determined using DNA samples donated by mass-screening participants and residents in Tokushima (n = 100) and Akita (n = 100), Japan. Haplotype constructions of the chromosome carrying R410 in the heterozygotes were conducted on the basis of Mendelian inheritance from their parents.

This study was conducted with approval of the Institutional Review Board for Kyoto University, School of Medicine. Written informed consent was obtained from all participants or the parents of participants under the age of consent.

R410X Detection and Genotyping. About 20 [mu]L of blood was spotted on blotter paper as described previously (Koizumi et al. 1998). These samples served as DNA sources as previously described by Lin et al (1993). Briefly, a 1 x 1 mm square of dried blood was placed in a polymerase chain reaction (PCR) tube. Each specimen was fixed by covering it with 10 [mu]L of methanol and letting the methanol evaporate at room temperature over half a day. Razors used to cut the blood spots were wiped, between samples, with 70% ethanol.

PCR amplification of the screened gene was carried out using the primer pair 9F (5'-GGC ATT GAT CTA CTT GTG CG-3') and 8/9R (5'-CAA CTC CAG CTG TTT CAG GT-3') under the conditions previously described (Koizumi et al. 2000). The generated PCR products were then digested with Taq 1. Normal alleles have two Taq 1 sites, while the R410X mutation (C[arrow right]T transition: CGA[arrow right]TGA) disrupts one Taq 1 site resulting in a restriction fragment length polymorphism.

Allele B Detection and Genotyping. PCR amplification of allele A and allele B was carried out using the primers 8FA (5'-AAT CCA AAT GCT CTA AGG AA-3'), 8FB (5'-AAT CCA AAT GAG CTC TGC TC-3'), and 8/9R (5'-CAA CTC CAG CTG TTT CAG GT-3') (Noguchi et al. 2000). To clarify the allelic sequences for each diploid genome, two sets of allele-specific PCRs were conducted using two primer pairs, 8FA and 8/9R, and 8FB and 8/9R. The generated PCR products were then digested with Taq 1 as previously reported (Noguchi et al. 2000).

Genotyping and Haplotype Construction in Proband Pedigrees. Two polymorphic microsatellite markers (D14S990 and D14S283) in the vicinity of the SLC7A7 gene (Lauteala et al. 1997) were selected for genotyping. The DNAs of the participants were genotyped by PCR amplification using 60 ng of each individual's DNA in a final volume of 15 [mu]L, followed by capillary electrophoresis on an ABI PRISM 310 genetic analyzer (ABI, NJ).

Estimating of the Age of Mutation. The Luria-Delbruck formula was used to estimate the number of generations since the introduction of the ancestral chromosome (Lauteala et al. 1997), with the assumption that the mutation rate ([mu]) of the LPI locus is 10^sup -6^.

P^sub excess^ = (1 - [mu]gq^sup -1^)(1 - [theta])^sup g^,

where [theta] is the probability of recombination fraction between given markers or genes, g is the number of generations since the introduction of the ancestral chromosome, [mu] is the mutation rate of the LPI locus, and q is the LPI gene frequency.

P^sub excess^ is the allelic excess calculated by use of the equation

where P^sub N^ is the frequency of the selected allele at the marker locus in the normal chromosome, and P^sub D^ is the higher frequency of the same allele in chromosomes carrying the disease mutation.

We assumed the mutation age as g x 20 years on the assumption of a 20-year period per generation.

Since [mu] was very small in comparison with g and q. Equation (1) was approximated by

P^sub excess^ = (1 - [theta])^sup g^,

where g = ln(P^sub excess^)/ln(1 - [theta]).

Two polymorphic markers (D14S283 and D14S990) in the vicinity of the SLC7A7 gene were selected to estimate g.

Estimation of g and Its Confidence Intervals. To obtain confidence intervals for an age of the mutation (g) for observed P^sub excess^ values of allele B and R410X, we conducted Monte Carlo computer simulation. We first simulated the number (N) of recombinations between markers D14S990 or D14S283 and allele B or R410X of SLC7A7 for 100 chromosomes after a given generation g (i.e., g meiotic events). The recombination event per meiosis was simulated as follows: If a random number [0,1] generated by a computer is larger than the probability of a recombination fraction, [theta], recombination took place, while in other cases it did not. The meiotic events were repeated for a given g for 100 chromosomes. The g was changed from 1 to 300. Repeated simulations gave various pairs of P^sub excessj^ and g^sub i^: (P^sub excessj^, g^sub i^). In the next step, we focused our attention on variations of g^sub j^ for an observed P^sub excess^. There are various g^sub s^ for an observed P^sub excess^, giving means and 95th percentile of gs for a given P^sub excess^. The program was written and run in SAS software (SAS Release 6.12, SAS Institute, Inc., Cary, NC).


We found a total of 39 chromosomes carrying R410X, 16 of which were derived from probands and the remaining 23 from heterozygotes. Allele-B-specific PCR products in those chromosomes revealed that the R410X mutations were exclusively on chromosomes with allele B, showing the complete concordance between the R410X mutation and allele B. Genotype frequencies of AA, AB, and BB for wild-type chromosomes were distributed in accordance with Hardy-Weinberg equilibrium (Table 1).

To estimate the age of the B mutation (an 8-bp deletion in intron 8), we determined the allelic variations at D14S990 and D14S283 of chromosomes carrying allele B. DNA samples donated by the probands and their parents enabled us to determine haplotypes with certainty. Analysis revealed that there was a weak yet discernible linkage disequilibrium between allele B and allele 8 of D14S990, while there was no such linkage disequilibrium between allele B and allele 4 of D14S283 (Table 2). The P^sub excess^ for D14S990, 0.123, gave an estimated age of the mutation of allele B as more than 300 generations by simulation. The age of the mutation, however, could not be estimated from the recombination between D14S283 and SLC7A7.

We next estimated the age of mutation of R410X using P^sub excesses^ for D14S990 and D14S283 (Table 3). There was strong linkage disequilibrium between R410X and allele 5 of D14S990 or allele 2 of D14S283. These data suggest that the founder haplotype of the R410X mutation was 5(D14S990)-B-R410X-2(D14S283). The age of the R410X mutation was estimated to 68 generations (95% confidence interval, 44-97) and 77 generations (95% confidence interval, 59-99) from P^sub excesses ^ for D14S990 and D14S283, respectively.

The allele B frequencies in three areas, Iwate, Akita, and Tokushima, are shown in Table 1. These frequencies were almost the same (approximately 10%-20%), indicating that allele B had spread widely over the Japanese Archipelago during the middle Jyomon period (4000-8000 B.C.).

In order to test whether the R410X mutation had spread, we searched for the R410X mutation in LPI patients throughout Japan. A case was known, a heterozygote compound of the pathological mutation of SLC7A7, R410X and 911+1 (G[arrow right]A). The proband's father was shown to be a carrier of R410X. Allele-specific PCR revealed that the R410X mutation in this proband was on allele B. The father and his ancestors were originally from the Gifu area (Figure 1) (personal communication from Dr. Teramoto, Dr. Fukao, and Prof. Kondo, Department of Pediatrics, Gifu University School of Medicine).


In the present study, we first demonstrated that the R410X mutation of SLC7A7 was in complete linkage disequilibrium with allele B, defined by an 18-bp deletion in intron 8. Analyses of the ages of these mutations suggest that the latter mutation occurred more than 6000 years ago, and the former mutation occurred over 1000 to 1500 years ago on a chromosome carrying the latter mutation. The distribution of R410X was entirely confined to a population in the northern part of Iwate (Koizumi et al. 2000), while that of allele B is widespread throughout Japan. The founder haplotype carrying R410X is estimated as 5-B-2 (D14S990-Intron 8 of SLC7A7-D14S283), which is a minor haplotype (less than 5%) among the population in Iwate.

Based on the above observations, we are tempted to hypothesize a historical lineage of R410X. At first, there was a population with an 18-bp deletion in intron 8 (allele B) in chromosome 14, and this mutation spread over the Japanese Archipelago (we estimated it would take some time to spread widely throughout Japan). The R410X mutation occurred in one person, a founder, who carried the B allele. It should also be kept in mind that a proband from Gifu had the founder R410X mutation specific to the northern part of Iwate. It is particularly interesting that there is an excess of cases in the Nagoya area, which is very close to Gifu (Kato et al. 1984). Therefore, there may be at least two possibilities for the origin of the R410X mutation. The first possibility is that the mutation occurred in the founder in Iwate and offspring migrated to the middle of Japan in a later era. The second possibility, the reverse of the first, is in agreement with historical records that describe some migration from the central part of Japan into the northern part in the Nara era (about A.D. 8th century). We cannot determine from the present study, however, which possibility is correct.

A reasonable question to ask is why the R410X mutation has been maintained in the population in Iwate. Historical records suggest that, as observed in other populations, consanguineous marriage was common. This custom in the northern part of Iwate was unique, however (Sato 1981). Briefly, the female offspring in a given family married males from a specific set of families, while the male offspring of the same family married females from a different set of families. Such traditional marriage loops among families have built very complicated pedigree webs in local communities, facilitating propagation of IBD (identical by descent) genes in the community. As a matter of fact, the HbM-Iwate mutation, which occurred in Nigremia, had been discovered in one town in the mass-screened area (Shibata et al. 1960; Obara 1963). Genetic isolation attributable to cultural, social, and geographical factors might be a factor that maintains genetic mutations in the northern part of Iwate.

It would be plausible, therefore, to expect that the genetic burden of LPI to the community would have been large, posing negative selection pressure for R410X. However, one must also consider the protein-deficient dietary regimen that was the norm in this area until the middle of the last century (Takanohashi 1964; Takanohashi 1965). The common daily diet was reported to be composed of 0-0.5 g of animal protein/day/kg and 2 g of grain protein/kg (barn millet and wheat) during childhood (Takanohashi 1964; Takanohashi 1965). This diet is essentially free from milk, meat, fish, and eggs, foods known to precipitate LPI symptoms and to be triggers of food rejection by children affected with LPI. Thus, traditional dietary habits could have very likely mitigated LPI symptoms and as a consequence rendered LPI a neutral mutation.

Finally, a remaining question would be whether the target population for mass screening is large enough to identify those at risk. Population mobility during the last 1000 years was kept to a minimum in Japan due mainly to the growth and enforcement of the feudal system. In particular, the feudal lords of the Nanbu family, ruling this area from the 13th to the 19th centuries, had forced people to settle and cultivate large tracts of virgin land while severely restricting travel. Thus, the spread of the R410X mutation started after the Meiji era (1867), in the last four to five generations at most. Thus, it is very likely that the present mass-screened population of 200,000, whose residential area is in the former sovereign territory of the lord Nanbu, may be large enough to cover the high-risk population.

In this study we could not clearly trace the population history of LPI in the communities examined. Future studies should include information on the population derived from other perspectives such as historical, linguistic, and cultural to eliminate the ambiguities inherent in the present study. As human beings change their lifestyle, so the dynamic of the disease might also change. In order to evaluate the various environmental factors that affect lifestyles, such multilevel studies will be needed. There may be other clusters of genetic mutations in Japan. As a source for the study of inheritance disorders, the population in Japan may have great potential.

Acknowledgments We are grateful to the members of the mass screening group: Professor Katsuichi Chida (Department of Pediatrics, Iwate Medical University), Professor Teruo Kagabu (Department of Obstetrics and Gynecology, Iwate Medical University), Dr. Hiroaki Sakai (Sakai Clinic), Dr. Eiki Tsukatani (Tsukatani Clinic), Drs. Tadashi Watanabe and Toshiaki Suzuki (Miyako Hospital), Dr. Kunio Ito (Ito Clinic), Dr. Masayuki Matsui (Matsui Clinic), Dr. Toshimitsu Takeshita (Takeshita Hospital), Dr. Masato Sekiyama (Director of the Department of Health and Welfare, Iwate Prefecture), and Dr. Kousei Ishikawa (Chairman of the Iwate Medical Association).

This project was supported by the Ministry of Education and Science of Japan through grants-in-aid B1247034 and B1270081 and by the Department of Welfare and Labor of Japan (H11-Chojyu-010) through a grant-in-aid on comprehensive research on aging and health. We are grateful to Dr. Sumiko Inoue, Ms. Umeko Oritani, Ms. Kayoko Inoue, and Ms. Maki Utsunomiya (Department of Health and Environmental Sciences, Kyoto University School of Public Health) for technical assistance.

Received 4 February 2002; revision received 20 September 2002.

Literature Cited

Borsani, G., M.T. Bassi, M.P. Sperandeo et al. 1999. SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Nat. Genet. 21:297-301.

DiRocco, M., G. Garibotto, G.A. Rossi et al. 1993. Role of haematological, pulmonary and renal complications in the long-term prognosis of patients with lysinuric protein intolerance. Eur. J. Pediatr. 152:437-440.

Incerti, B., G. Andria, G. Parenti et al. 1993. Lysinuric protein intolerance: Studies on 17 Italian parents. Am. J. Hum. Genet. Suppl. 53:908.

Kamoda, T., Y. Nagai, M. Shigeta et al. 1998. Lysinuric protein intolerance and systemic lupus erythematosus. Eur. J. Pediatr. 157:130-131.

Kato, T., N. Mizutani, and M. Ban. 1984. Hyperammonemia in Lysinuric Protein Intolerance. Pediatrics 73:489-492.

Koizumi, A., Y. Shoji, J. Nozaki et al. 2000. A cluster of lysinuric protein intolerance (LPI) patients in a northern part of Iwate, Japan due to a founder effect. Hum. Mut. 16:270-271.

Koizumi, A., T. Nomiyama, M. Tsukada et al. 1998. Evidence on N-acetyltransferase allele-associated metabolism of hydrazine in Japanese workers. J. Occup. Environ. Med. 40:217-222.

Lauteala, T., P. Sistonen, M.L. Savontaus et al. 1997. Lysinuric Protein Intolerance (LPI) gene maps to the long arm of chromosome 14. Am. J. Hum. Genet. 60:1479-1486.

Lin, H.J., C. Han, B.K. Lin et al. 1993. Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, Blacks, Hispanics, and Whites: Application to metabolic epidemiology. Am. J. Hum. Genet. 52:827-834.

Noguchi, A., U. Shoji, A. Koizumi et al. 2000. Mutational analysis of SLC7A7 gene in three Japanese families with lysinuric protein intolerance. Hum. Mut. 15:367-372.

Obara, K. 1963. Metabolism of nigremia. J. Iwate Med. Ass. 14:223-228.

Perheentupa, J., and J.K. Visakorpi. 1965. Protein intolerance with deficient transport of basic amino acids. Lancet 23:813-816.

Sato, K. 1981. Kinship and Funeral Ceremonies in Miyako, Iwate. The Miyako City History. Folklore Ed., 800-842.

Shibata, S., A. Tamura, I. Iuchi et al. 1960. Hemoglobin M1: Demonstration of new abnormal hemoglobin in hereditary nigremia. Act. Hematol. Jap. 23:96-105.

Simell, O., J. Perheentupa, J. Rapola et al. 1975. Lysinuric protein intolerance. Am. J. Med. 59:229-240.

Simell, O. 2001. Lysinuric protein intolerance and other cationic aminoacidurias. In The Metabolic and Molecular Bases of Inherited Disease, C.R. Scriver, A.L. Beaudet, W.S. Sly et al., eds. 8th ed. New York, NY: McGraw-Hill Medical Publishing Division, 4933-4956.

Takanohashi, T. 1964. Studies on the dietary life of villages in cold and snowy districts. The Annual Report of the Faculty of Education, University of Iwate 23:41-79.

Takanohashi, T. 1965. Habitual diets of growing children and their improvement in the low-protein district. The Annual Report of the Faculty of Education, University of Iwate 25:95-118.

Torrents, D., J. Mykkanen. M. Pineda et al. 1999. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. Nat. Genet. 21:293-296.


1Department of Global Health and Socio-Epidemiology, Kyoto University, School of Public Health, Kyoto, 606-8501 Japan.

2Department of Health and Environmental Sciences, Kyoto University, School of Public Health, Kyoto, 606-8501 Japan.

3Department of Biostatistics, Kyoto University, School of Public Health, Kyoto, 606-8501 Japan.

4Morioka Children's Hospital, Morioka 020-0102, Japan.

5Mass screening group.

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