Guillaume Dorval1,2, Cécile Jeanpierre2, Vincent Morinière1, Carole Tournant1, Bettina Bessières3, Tania Attié-Bittach3,4, Jeanne Amiel4,5, Emmanuel Spaggari6, Yves Ville6,7, Elodie Merieau8, Marie-Claire Gubler2, Sophie Saunier2, Laurence Heidet9,10. 1. APHP, Service de Génétique moléculaire, Hôpital universitaire Necker-Enfants malades, F-75015, Paris, France. 2. Laboratory of Hereditary Kidney Diseases, Université de Paris, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France. 3. APHP, Embryofœtopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital universitaire Necker-Enfants malades, F-75015, Paris, France. 4. Université de Paris, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France. 5. APHP, Service de Génétique, Hôpital universitaire Necker-Enfants malades, F-75015, Paris, France. 6. APHP, Service d'Obstétrique et Médecine fœtale, Hôpital universitaire Necker-Enfants malades, F-75015, Paris, France. 7. EA 7328, Université de Paris, Paris, France. 8. Service de Néphrologie pédiatrique, Hôpital universitaire de Tours, Tours, France. 9. Laboratory of Hereditary Kidney Diseases, Université de Paris, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France. laurence.heidet@aphp.fr. 10. APHP, Service de Néphrologie pédiatrique, Centre de Référence MARHEA, Hôpital universitaire Necker-Enfants malades, 149 rue de Sèvres, F-75015, Paris, France. laurence.heidet@aphp.fr.
Abstract
BACKGROUND: Co-occurrence of polycystic kidney disease and hyperinsulinemic hypoglycemia has been reported in children in a few families associated with a variant in the promotor of the PMM2 gene, at position -167 upstream of the coding sequence. PMM2 encodes phosphomannomutase 2, a key enzyme in N-glycosylation. While biallelic coding PMM2 mutations are involved in congenital disorder of glycosylation CDG1A, that particular variant in the promoter of the gene, either in the homozygous state or associated with a mutation in the coding exons of the gene, is thought to restrict the N-glycosylation defect to the kidney and the pancreas. METHODS: Targeted exome sequencing of a panel of genes involved in monogenic kidney diseases. RESULTS: We identified a PMM2 variant at position -167 associated with a pathogenic PMM2 variant in the coding exons in 3 families, comprising 6 cases affected with a cystic kidney disease. The spectrum of phenotypes was very broad, from extremely enlarged fetal cystic kidneys in the context of a COACH-like syndrome, to isolated cystic kidney disease with small kidneys, slowly progressing toward kidney failure in adulthood. Hypoglycemia was reported only in one case. CONCLUSION: These data show that the PMM2 promotor variation, in trans of a PMM2 coding mutation, is associated with a wide spectrum of kidney phenotypes, and is not always associated with extra-renal symptoms. When present, extra-renal defects may include COACH-like syndrome. These data prompt screening of PMM2 in unresolved cases of fetal hyperechogenic/cystic kidneys as well as in cystic kidney disease in children and adults. Graphical Abstract.
BACKGROUND: Co-occurrence of polycystic kidney disease and hyperinsulinemic hypoglycemia has been reported in children in a few families associated with a variant in the promotor of the PMM2 gene, at position -167 upstream of the coding sequence. PMM2 encodes phosphomannomutase 2, a key enzyme in N-glycosylation. While biallelic coding PMM2 mutations are involved in congenital disorder of glycosylation CDG1A, that particular variant in the promoter of the gene, either in the homozygous state or associated with a mutation in the coding exons of the gene, is thought to restrict the N-glycosylation defect to the kidney and the pancreas. METHODS: Targeted exome sequencing of a panel of genes involved in monogenic kidney diseases. RESULTS: We identified a PMM2 variant at position -167 associated with a pathogenic PMM2 variant in the coding exons in 3 families, comprising 6 cases affected with a cystic kidney disease. The spectrum of phenotypes was very broad, from extremely enlarged fetal cystic kidneys in the context of a COACH-like syndrome, to isolated cystic kidney disease with small kidneys, slowly progressing toward kidney failure in adulthood. Hypoglycemia was reported only in one case. CONCLUSION: These data show that the PMM2 promotor variation, in trans of a PMM2 coding mutation, is associated with a wide spectrum of kidney phenotypes, and is not always associated with extra-renal symptoms. When present, extra-renal defects may include COACH-like syndrome. These data prompt screening of PMM2 in unresolved cases of fetal hyperechogenic/cystic kidneys as well as in cystic kidney disease in children and adults. Graphical Abstract.
Authors: S Romano; F Bajolle; V Valayannopoulos; S Lyonnet; V Colomb; C de Baracé; P Vouhe; P Pouard; S Vuillaumier-Barrot; T Dupré; Y de Keyzer; D Sidi; N Seta; D Bonnet; P de Lonlay Journal: J Med Genet Date: 2009-04 Impact factor: 6.318
Authors: G Matthijs; E Schollen; C Bjursell; A Erlandson; H Freeze; F Imtiaz; S Kjaergaard; T Martinsson; M Schwartz; N Seta; S Vuillaumier-Barrot; V Westphal; B Winchester Journal: Hum Mutat Date: 2000-11 Impact factor: 4.878
Authors: P Briones; M A Vilaseca; M T García-Silva; M Pineda; J Colomer; I Ferrer; J Artigas; J Jaeken; A Chabás Journal: Eur J Paediatr Neurol Date: 2001 Impact factor: 3.140
Authors: Sumaya Islam; Mehmet Tekman; Sarah E Flanagan; Lisa Guay-Woodford; Khalid Hussain; Sian Ellard; Robert Kleta; Detlef Bockenhauer; Horia Stanescu; Daniela Iancu Journal: Mol Genet Genomic Med Date: 2021-04-03 Impact factor: 2.473