Yue-Qiu Tan1,2,3, Chaofeng Tu1,3, Lanlan Meng1,3, Shimin Yuan1,3, Calvin Sjaarda4, Aixiang Luo1,3, Juan Du1,2,3, Wen Li1,2,3, Fei Gong1,2,3, Changgao Zhong1,2,3, Han-Xiang Deng5, Guangxiu Lu3, Ping Liang6, Ge Lin7,8,9. 1. Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. 2. Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. 3. Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. 4. Department of Biological Sciences, Brock University, St. Catharines, Ontario, Canada. 5. Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 6. Department of Biological Sciences, Brock University, St. Catharines, Ontario, Canada. pliang@brocku.ca. 7. Institute of Reproductive and Stem Cell Engineering, College of Basic of Medicine, Central South University, Changsha, China. linggf@hotmail.com. 8. Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. linggf@hotmail.com. 9. Key Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, China. linggf@hotmail.com.
Abstract
PURPOSE: Comorbid familial nonobstructive azoospermia (NOA) and congenital cataract (CC) have not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose was to uncover novel human mutations and genes causing familial NOA and CC. METHODS: We performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7. RESULTS: Two novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and c.688_689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient's seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome. CONCLUSION: We identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.
PURPOSE: Comorbid familial nonobstructive azoospermia (NOA) and congenital cataract (CC) have not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose was to uncover novel human mutations and genes causing familial NOA and CC. METHODS: We performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7. RESULTS: Two novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and c.688_689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient's seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome. CONCLUSION: We identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.
Authors: Hélène Choquet; Ronald B Melles; Deepti Anand; Jie Yin; Gabriel Cuellar-Partida; Wei Wang; Thomas J Hoffmann; K Saidas Nair; Pirro G Hysi; Salil A Lachke; Eric Jorgenson Journal: Nat Commun Date: 2021-06-14 Impact factor: 14.919