doi: 10.1111/ahg.12116 Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families Irfanullah 1 , Muhammad Umair 1 , Saadullah Khan 2 and Wasim Ahmad 1∗ 1 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Pakistan 2 Department of Biotechnology & Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan Summary Acromesomelic dysplasia Maroteaux type (AMDM) is an autosomal recessive skeletal disorder characterized by dispro- portionate short stature with shortening of the acromesomelic sections of the limbs. AMDM is caused by mutations in the NPR2 gene located on chromosome 9p21-p12. The gene encodes the natriuretic peptide receptor B (NPR-B) that acts as an endogenous receptor for C-type natriuretic peptide (CNP). Both CNP and NPR-B are considered as important regulators of longitudinal growth. The study presented here investigated three consanguineous families (A, B, C) segregating AMDM in an autosomal recessive manner. Linkage in the families was established to the NPR2 gene on chromosome 9p12-21. Sequence analysis of the gene revealed two novel missense variants (p.Arg601Ser; p.Arg749Trp) in two families and a previously reported splice site variant (c.2986+2T>G) in the third family. Keywords: Acromesomelic dysplasia-type Maroteaux, consanguineous families, NPR2 gene, missense and splice site variants Introduction Acromesomelic dysplasias represent a group of skeletal disor- ders characterized by disproportionate shortening of skeletal elements, mainly affecting the middle parts of the forearms and forelegs, and distal segments (hands and feet) of the appen- dicular skeleton. On the basis of phenotypic and radiologic variability recorded in patients, acromesomelic dysplasias are categorized into three types: acromesomelic dysplasia type Grebe (AMDG) (MIM #200700), acromesomelic dysplasia type Hunter and Thompson (AMDH) (MIM #201250) and acromesomelic dysplasia Maroteaux type (AMDM) (MIM #602875) (Grebe, 1952; Maroteaux et al., 1971; Hunter & Thompson, 1976). AMDM is an autosomal recessive disorder that can be dis- tinguished clinically from other types of acromesomelic dys- plasias (Maroteaux et al., 1971; Langer et al., 1989; Costa ∗ Corresponding author: WASIM AHMAD, Department of Bio- chemistry, Faculty of Biological Sciences, Quaid-i- Azam Uni- versity Islamabad, Pakistan. Tel: +92-51-90643003; E-mail: wahmad@qau.edu.pk et al., 1998). Clinical features of AMDM, reported in the patients, include disproportionate short stature with height below 120 cm and noticeable shortening of middle and dis- tal segments of the skeleton (Maroteaux et al., 1971; Langer & Garrett, 1980). Radiographic features of AMDM patients revealed short ulna with hypoplastic distal end. The skull is usually dolichocephalic with shortness of the trunk and re- duced vertebral height without any associated facial or mental abnormalities (Langer & Garrett, 1980). Kant et al. (1998) mapped AMDM on human chromosome 9p21-p12. Bartels et al. (2004) later reported 21 mutations in the NPR2 gene underlying AMDM in 21 different families. The NPR2 gene is located on chromosome 9p21-p12 and encodes the natriuretic peptide receptor B (NPR-B). This receptor is a member of a group of three natriuretic peptide receptors (NPR-A, NPR-B, NPR-C), which bind with natriuretic peptide hormones and regulate a number of physiological processes including cardiac growth, blood pressure, axonal path finding and endochondral ossification (Kishimoto et al., 2001; Tamura et al., 2004; Langenickel et al., 2006). Several studies validated that CNP-NPR2 signaling plays an important role in endochondral ossification and its inactivation resulted in dwarfism in both mouse and 238 Annals of Human Genetics (2015) 79,238–244 C  2015 John Wiley & Sons Ltd/University College London