Type I Hyperprolinemia: Genotype/Phenotype Correlations

Inserm U614, IHU, 76000 Rouen, France.
Human Mutation (Impact Factor: 5.14). 08/2010; 31(8):961-5. DOI: 10.1002/humu.21296
Source: PubMed


Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity, and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. Eight of 14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for six novel mutations and two haplotypes. The c.1331G>A, p.G444D allele has a drastic effect, whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity <50%. Eight out of nine subjects with a predicted residual activity > or = 50% bore at least one c.824C>A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.

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Available from: Vassili Valayannopoulos
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    • "Moreover, the relationship between blood and brain proline levels and the role played by the blood–brain barrier is still an open question (Hawkins et al., 2006). Nonspecific dysmorphisms reported in some HPI patients might suggest a role of HPI in syndromic mental retardation (Guilmatre et al., 2010). This finding was evident in four out of 10 patients (40%). "
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    ABSTRACT: The neuropsychiatric phenotype associated with hyperprolinemia type I (HPI) is still under debate. To our knowledge, no long-term follow-up on patients with HPI has been reported so far. We have previously described the clinical, biochemical, and molecular features of four patients with HPI. Here, we report on the neuropsychiatric and genotype features of an expanded sample of 10 patients with HPI with a mean follow-up duration of 11 years. Epileptic manifestations and/or cognitive impairment were prevalent at onset, but they were subsequently replaced by psychiatric disorders. Social behavior and relational skills were considerably impaired in the majority of cases. Learning disability was present in one patient. The complex neurochemical effects of proline on the central nervous system and genotype/phenotype correlations were discussed.
    Full-text · Article · May 2014 · European Journal of Paediatric Neurology
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    • "There is also a strong association between schizophrenia and 22q11DS and/or microdeletions of 22q11 encompassing the PRODH locus (Karayiorgou et al. 2010), and it has been suggested that 22q11DS may be under-diagnosed (McDonald-McGinn et al. 2005). However, whilst our study subjects were not genotyped for PRODH variants, based upon the frequency of subjects with hyperprolinemia (26.6%), abnormal proline homeostasis may also be implicated, rather than higher than expected prevalence of 22q11DS or functional PRODH nucleotide variants (Guilmatre et al. 2010). "
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