Fly model helps illuminate mechanisms underlying contribution of GEMIN4 in an inherited neurodevelopmental disorder

Am J Med Genet A. 2022 Oct;188(10):2932-2940. doi: 10.1002/ajmg.a.62894 

Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome

Altassan R, Qudair A, Alokaili R, Alhasan K, Faqeih EA, Alhashem A, Alowain M, Alsayed M, Rahbeeni Z, Albadi L, Alkuraya FS, Anderson EN, Rajan D, Pandey UB

Abstract:

Pathogenic variants in GEMIN4 have recently been linked to an inherited autosomal recessive neurodevelopmental disorder characterized with microcephaly, cataracts, and renal abnormalities (NEDMCR syndrome). This report provides a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 mutations. The cohort comprises 11 new and unpublished clinical details from five previously described patients. Only two missense, homozygous, pathogenic variants were found in all affected patients, suggesting a founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. In addition, we knocked down endogenous Drosophila GEMIN4 in neurons to further investigate the mechanism of the functional defects in affected patients. Our fly model findings demonstrated developmental defects and motor dysfunction suggesting that loss of GEMIN4 function is detrimental in vivo; likely similar to human patients. To date, this study presents the largest cohort of patients affected with GEMIN4 mutations. Considering that identifying GEMIN4 defects in patients presenting with neurodevelopmental delay and congenital cataract will help in early diagnosis, appropriate management and prevention plans that can be made for affected families.

DOI: 10.1002/ajmg.a.62894
PMID: 35861185

Drosophila studies contributed to -- another -- study that identifies a human disease gene

Ansar M, Chung HL, Taylor RL, Nazir A, Imtiaz S, Sarwar MT, Manousopoulou A, Makrythanasis P, Saeed S, Falconnet E, Guipponi M, Pournaras CJ, Ansari MA, Ranza E, Santoni FA, Ahmed J, Shah I, Gul K, Black GC, Bellen HJ, Antonarakis SE. Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts. Am J Hum Genet. 2018 Oct 4;103(4):568-578. PMID: 30290152; PMCID: PMC6174361.

From the abstract: "Infantile and childhood-onset cataracts form a heterogeneous group of disorders; among the many genetic causes, numerous pathogenic variants in additional genes associated with autosomal-recessive infantile cataracts remain to be discovered. We identified three consanguineous families affected by bilateral infantile cataracts. Using exome sequencing, we found homozygous loss-of-function variants in DNMBP ... The phenotypes of all affected individuals include infantile-onset cataracts. RNAi-mediated knockdown of the Drosophila ortholog still life (sif), enriched in lens-secreting cells, affects the development of these cells as well as the localization of E-cadherin, alters the distribution of septate junctions in adjacent cone cells, and leads to a ∼50% reduction in electroretinography amplitudes in young flies. ... We therefore conclude that DNMBP loss-of-function variants cause infantile-onset cataracts in humans."

Big thank you to the US NIH Office of Research Infrastructure Programs (ORIP) for support of projects that generated fly stocks and other resources used in this study.

Fly studies help shed light on contribution of KAT2B variants to ADD3-associated disorders

Gonçalves S, Patat J, Guida MC, Lachaussée N, Arrondel C, Helmstädter M, Boyer O, Gribouval O, Gubler MC, Mollet G, Rio M, Charbit M, Bole-Feysot C, Nitschke P, Huber TB, Wheeler PG, Haynes D, Juusola J, Billette de Villemeur T, Nava C, Afenjar A, Keren B, Bodmer R, Antignac C, Simons M. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies. PLoS Genet. 2018 May 16;14(5):e1007386. PMID: 29768408.

The abstract: "Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders."

New fly model: αB-crystallin-related cardiomyopathy. Recent report.

Xie HB, Cammarato A, Rajasekaran NS, Zhang H, Suggs JA, Lin HC, Bernstein SI, Benjamin IJ, Golic KG. The NADPH Metabolic Network Regulates Human αB-crystallin Cardiomyopathy and Reductive Stress in Drosophila melanogaster. PLoS Genet. 2013 PMID: 23818860.